Randomized Trial for Mixed Acute Rejection
Condition: Graft Rejection
Intervention: Rabbit Antithymocyte Globulin (RATG); Rituximab; Bortezomib; Acetaminophen; Antihistamine; Methylprednisolone
Intervention description: All patients will receive Thymoglobulin dosed based on CD3 count. Patients will be redosed when the CD3 count is ≥ 25. Depending on rejection severity, Thymoglobulin will be given for a maximum of 7-14 days. CD3 levels will be monitored daily.; Rituximab dose of 375 mg/ m2 on day 2. Patients will be premedicated with an antihistamine and acetaminophen prior to dosing per institution standard of care.; Patient will receive 1.3 mg/m2 via IV push over 3-5 seconds on days 2, 5, 9, and 12. Consolidation course of bortezomib will be dosed at 1.3 mg/m2 IVP X 4 doses administered on days 1, 4, 7 and 10.; Patients will be premedicated with acetaminophen prior to dosing per institution standard of care.; Patients will be premedicated with an antihistamine prior to dosing per institution standard of care.; Methylprednisolone 250 mg with 1st dose of Thymoglobulin. Methylprednisolone 125 mg on treatment day 2 subsequent corticosteroids per institution standard of care; following treatment, corticosteroid therapy will resume at the pre-rejection dose.
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Methylprednisolone; Rituximab; Bortezomib; Thymoglobulin; Antilymphocyte Serum; Histamine H1 Antagonists; Histamine Antagonists
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      This study is being conducted to determine how safe and effective using an immune cell (b
      cell) depleting therapy and/or Thymoglobulin is in patients with a kidney transplant who are
      experiencing certain types of rejection.
    

Eligibility criteria:

        Inclusion Criteria

        Each subject must meet all of the following inclusion criteria to be enrolled in the study:

          -  Voluntary written informed consent before performance of any study-related procedure
             not part of normal medical care, with the understanding that consent may be withdrawn
             by the subject at any time without prejudice to future medical care.

          -  Female subject is either post-menopausal or surgically sterilized or willing to use
             two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine
             device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
             duration of the study.

          -  Male subject agrees to use an acceptable method for contraception for the duration of
             the study.

          -  Subject is between 18 and 65 years of age, inclusive.

          -  Subject has a transplant dysfunction indicated by an increase in creatinine of 0.3
             mg/dL or 15% (lipase >3 X ULN for kidney/pancreas recipients) over baseline
             necessitating an allograft biopsy to assess for allograft rejection.

          -  Presence of light microscopic histologic changes consistent with acute cellular
             rejection of a Banff 97 (2005 update) grade IA or greater and at least one of the
             following:

          -  Donor-specific antibody (DSA) positive via Luminex

          -  Presence of C4d in the peritubular capillaries or glomeruli

          -  Subject must have no known contraindications to treatment with bortezomib, boron or
             mannitol, thymoglobulin, or rituximab.

          -  Recipients of kidney or simultaneous kidney pancreas organ transplant.

        Exclusion Criteria

        Subjects meeting any of the following exclusion criteria are not to be enrolled in the
        study.

          -  Subject has a platelet count < 100,000/mm3 within 7 days before enrollment.

          -  Subject has an absolute neutrophil count of < 1,000/mm3 within 7 days before
             enrollment.

          -  Subject has Grade 2 peripheral neuropathy within 14 days before enrollment.

          -  Myocardial infarction within 6 months prior to enrollment or has New York Heart
             Association (NYHA) Class III or IV heart failure (see section 8.4), uncontrolled
             angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
             of acute ischemia or active conduction system abnormalities. Prior to study entry, any
             ECG abnormality at Screening has to be documented by the investigator as not medically
             relevant.

          -  Subject has received other investigational drugs with 14 days before enrollment

          -  Serious medical (other than renal disease) or psychiatric illness likely to interfere
             with participation in this clinical study.

          -  Subjects that have previously received an organ transplant other than kidney or
             simultaneous kidney pancreas.

          -  Subjects who are recipients of A-B-O incompatible transplants, all cytotoxicity (CDC)
             crossmatch positive transplants

          -  Recipients of a simultaneous kidney pancreas transplant that only have pancreas
             rejection.

          -  Subjects unable to tolerate a dose of mycophenolate mofetil 1-3g/day (or equivalent
             mycophenolic acid dose).

          -  Subjects who are anti-HIV-positive, or HBsAg-positive. Anti-Hepatitis C Virus (HCV)
             positive patients are excluded, except patients with negative pathologic complete
             remission-result.

          -  Recipients of a kidney from a donor who tests positive for HIV, HBsAg or anti-HCV

          -  History of malignancy within the past 5 years that is not considered to be cured, with
             the exception of localized basal cell carcinoma of the skin (excised ≥ 2 years prior
             to randomization)

          -  Subjects with current or recent severe systemic infections within the 2 weeks prior to
             randomization.

          -  Receipt of a live vaccine within 4 weeks prior to study entry

          -  Evidence of severe liver disease with abnormal liver profile (aspartate
             aminotransferase (AST), alanine aminotransferase (ALT) or total bilirubin > 3 times
             upper limit of normal (ULN)) at screening.

          -  Pregnant or nursing (lactating) women.

          -  EBV sero-mismatch (EBV + donor organ transplanted to EBV - recipient)

          -  CMV sero-mismatch (CMV + donor organ transplanted to CMV - recipient)