Use of Immune Globulin Plus Rituximab for Desensitization in Highly HLA Sensitized Patients Awaiting Deceased Donor Kidney Transplantation

This single center, Phase I/II, exploratory study has been modified to a safety/efficacy study providing all patients with IVIG and Rituximab. The trial will examine the safety and efficacy of human polyclonal IVIG 10%, when given at \[2.0 gm/kgx2\], + Rituximab 1gm to reduce donor-specific antibodies (DSA) to a level that is permissive for transplantation in 75 subjects (adults only ages \>18 yrs) who are highly-HLA sensitized and are awaiting deceased donor kidney transplant. Once transplant offers are entertained, a donor-specific crossmatch will be performed. If acceptable crossmatches and DSA levels are seen, the patients will proceed to DD transplantation. Patients receiving transplants will receive an additional dose of IVIG at transplantation (within 10 days) and will receive additional doses of Rituximab 1g at 3M post transplant if DSA levels remain or become positive at 6M if de novo DSA occur. Patients who are desensitized and not transplanted at 9M after desensitization will have completed the study and can be treated as best judged by their physician.

Organ transplantation offers the only hope for a normal life for patients with end-stage renal disease on dialysis. For patients with antibodies to human leukocyte antigens (HLA), transplantation is extremely difficult or impossible since pre-formed antibodies will cause severe rejection and loss of transplanted organs. Intravenous gamma globulin (IVIG) can reduce or eliminate these antibodies in most patients and allow for successful transplantation. This breakthrough has allowed patients previously considered not transplantable to receive life-saving transplants. However, IVIG alone does not always eradicate the anti-HLA antibodies to a degree that will allow transplantation.

In this study, the investigators propose additional treatment with rituximab, a humanized antibody directed at the CD20 antigen that is present on most B-cells. Both IVIG and rituximab are approved by the U.S. Food and Drug Administration (FDA) for numerous immunologic disorders and Non-Hodgkin's lymphoma, respectively. However, neither is approved by the FDA for desensitization of highly-HLA sensitized transplant patients. A previously conducted pilot study demonstrated IVIG + Rituximab can fill an important gap in the current therapeutic approach for management of highly sensitized patients and may become the standard therapy.

Update: Study updated after observation that subjects transplanted after desensitization with IVIG alone experienced higher rates of antibody rejection and graft loss. The primary objective of this revised protocol will be to examine the safety and efficacy of IVIG 2gm/kg (maximum 140g) given on day#0 \& day #30 plus Rituximab 1gm given on day #15. Transplanted patients will receive additional doses of Rituximab 1gm at 3 months post-transplant if donor specific antibody (DSA) levels remain or become positive or at 6M if de novo DSA occur. All transplanted patients who remain DSA negative, will not receive additional Rituximab. All transplanted patients will have a protocol biopsy at transplant and 12 months. All subjects will complete 5 visits in the pre-transplant phase of the study. Patients who are transplanted will have additional 5 post-transplant visits. The following are research-related procedures:

1. Rituximab infusion.
2. Kidney allograft biopsies (Intra-op, 12 months post-transplant)
3. Rituximab level, HACA levels
4. Immunologic biomarkers (CD19+, CD38+, CD27+)

Although the investigator commonly uses both treatment regimens at Cedars-Sinai Medical Center, only the IVIG treatment is considered to be standard of care for highly HLA-sensitized patients. The investigational component of this study is the addition of the rituximab. Currently the study has been amended to a safety and efficacy study focusing on decreasing HLA antibodies pre-transplant and minimizing DSA post-transplant.

Eligibility Criteria:
Inclusion Criteria:

1. End-stage renal disease.
2. No known contraindications for therapy with IGIV10%/Rituximab.
3. Age 18-70 years at the time of screening.
4. PRA\> 30% demonstrated on 3 consecutive samples, UNOS wait time sufficient to allow DD offers, history of sensitizing events, positive crossmatch with the intended donor.
5. Subject/Parent/Guardian must be able to understand and provide informed consent.

Exclusion Criteria:

1. Lactating or pregnant females.
2. Pediatric patients \<18 years of age
3. Women of child-bearing age who are not willing or able to practice FDA-approved forms of contraception.
4. HIV-positive subjects.
5. Subjects who test positive for HBV infection \[positive HBVsAg, HBVcAg, or HBVeAg/DNA\] or HCV infection \[positive Anti-HCV (EIA) and confirmatory HCV RIBA\].
6. Subjects with active TB.
7. Subjects with selective IgA deficiency, those who have known anti-IgA antibodies, and those with a history of anaphylaxis or severe systemic responses to any part of the clinical trial material.
8. Subjects who have received or for whom multiple organ transplants are planned.
9. Recent recipients of any licensed or investigational live attenuated vaccine(s) within two months of the screening visit (including but not limited to any of the following:

   * Adenovirus \[Adenovirus vaccine live oral type 7\]
   * Varicella \[Varivax\]
   * Hepatitis A \[VAQTA\]
   * Rotavirus \[Rotashield\]
   * Yellow fever \[Y-F-Vax\]
   * Measles and mumps \[Measles and mumps virus vaccine live\]
   * Measles, mumps, and rubella vaccine \[M-M-R-II\]
   * Sabin oral polio vaccine
   * Rabies vaccines \[IMOVAX Rabies I.D., RabAvert\])
10. A significantly abnormal general serum screening lab result defined as a WBC \< 3.0 X 103/ml, a Hgb \< 8.0 g/dL, a platelet count \< 100 X 103/ml, , an SGOT \> 5X upper limit of normal, and an SGPT \>5X upper limit of normal range.
11. Individuals deemed unable to comply with the protocol.
12. Subjects with active CMV or EBV infection as defined by CMV-specific serology (IgG or IgM) and confirmed by quantitative PCR with or without a compatible illness.
13. Subjects with a known history of previous myocardial infarction within one year of screening.
14. Subjects with a history of clinically significant thrombotic episodes, and subjects with active peripheral vascular disease.
15. Use of investigational agents within 4 weeks of participation.