CAMPath and BELimumab for Transplant Tolerance in Sensitized Kidney Transplant Recipients
Condition: Kidney Transplantation
Intervention: Belimumab
Intervention description: Kidney transplant recipients (n=5) will receive standard of care (SOC) therapy consisting of alemtuzumab and steroid induction with mycophenolic acid and tacrolimus maintenance immunosuppression, plus induction and treatment for 6 months with belimumab.
Intervention MeSH terms: Belimumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Intervention model description: This study is proposed to be an open-label, single-arm, pilot study to test whether the addition of belimumab, to inhibit the B cell survival factor BLyS at the time of kidney transplantation, to standard or care therapy (alemtuzumab and steroid induction with mycophenolic acid and tacrolimus maintenance immunosuppression) will prevent the prevent the generation of de novo DSA
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Donor Specific Antibody; Donors, Living; Allograft Tolerance

Summary:

      The purpose of this research study is to determine whether kidney transplant recipients who
      receive belimumab (Benlysta®), combined with the standard of care medications for kidney
      transplant recipients, is safe and effective in helping prevent new donor specific antibodies
      (DSA) after transplantation. The presence of DSA increases the risk that the kidney
      transplant recipient's body will reject the new kidney. The investigators are doing this
      research because it is estimated that greater than 50% of kidney transplant failures are
      attributed to antibodies produced in the body, that attack the transplanted organ as a
      foreign object. DSA produced in the body after a kidney transplant, is thought to occur in
      20-50% of patients and is associated with a low likelihood that the organ recipient's body
      will accept the new kidney. A major unmet need in the kidney transplant area are safe and
      effective therapies to prevent DSA after transplantation.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female subjects 18-60 years of age

          -  Planned to receive a deceased or living donor kidney transplant

          -  Sensitized patients: Positive sum DSA <1000, and/or PRA>0%.

          -  Subjects must be capable of understanding the purpose and risks of the study and must
             sign a statement of informed consent.

          -  Female subjects must be post-menopausal, surgically sterilized, or she and/or sexual
             partner must be willing to use an acceptable method of birth control with a <1%
             failure rate as stated in the product label from time of study consent, during study
             participation, and for 16 weeks after the last dose of the study agent (i.e.,
             contraceptive subdermal implant of levonorgestrel or etonogestrel, intrauterine device
             or intrauterine system, combined estrogen and progestogen oral contraceptive,
             Injectable progestogen, contraceptive vaginal ring, percutaneous contraceptive
             patches, or abstinence) for the duration of the study. Male partner sterilization with
             documentation of azoospermia prior to the female subject's entry into the study, and
             this male is the sole partner for that subject. The documentation of male sterility
             can come from the site personnel's: review of subject's medical records, medical
             examination and/or semen analysis, or medical history interview provided by her or her
             partner. Note: Mycophenolate mofetil (MMF) affects the metabolism of oral
             contraceptives and may reduce their effectiveness. As such, women receiving MMF who
             are using oral contraceptives for birth control should employ an additional method
             (e.g., barrier method). Mycophenolate can cause fetal harm when administered to a
             pregnant female. Use of mycophenolate during pregnancy is associated with an increased
             risk of first trimester pregnancy loss and an increased risk of congenital
             malformations. Mycophenolate affects the metabolism of oral contraceptives and may
             reduce their effectiveness. As such, women receiving MMF who are using oral
             contraceptives for birth control should employ an additional method (e.g., barrier
             method) resulting in two reliable forms of contraception being used simultaneously
             before starting study treatments, during therapy, and for 6 weeks after stopping
             therapy; unless abstinence is the chosen method of contraception

          -  Female patients of childbearing potential must have a negative serum pregnancy test
             within 48 hours of transplant. Must be willing to use contraceptives from the time of
             study consent, during study participation, and for 16 weeks after the last dose of
             study agent. For sexually active men, condoms should be used during, and for at least
             90 days after cessation of mycophenolate treatment. No sperm donation should be made
             during this period of time. For female partners of male subjects, it is recommended to
             use highly effective contraception during treatment and for 90 days after the last
             dose of mycophenolate

          -  No blood donation should be made by the study subjects during mycophenolate treatment
             and for at least 6 weeks after stopping mycophenolate treatment

          -  If stricter female or male contraception requirements are specified in the
             country-specific label for any study related therapies, they must be followed.

          -  Male subjects must agree to use an acceptable method for contraception for the
             duration of the study.

        Female patients of childbearing potential must have a negative serum pregnancy test within
        48 hours of transplant. Must be willing to use contraceptives from the time of study
        consent, during study participation, and for 16 weeks after the last dose of study agent.
        Reproductive Status: Definition of Women of Child-Bearing Potential (WOCBP). WOCBP
        comprises women who have experienced menarche and who have not undergone successful
        surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy)
        or who are not post-menopausal (see definition below).

        Post-menopause is defined as:

          -  Women who have had amenorrhea for greater than or equal to 12 consecutive months
             (without another cause) and who have a documented serum follicle-stimulating hormone
             (FSH) level > 35 mIU/mL.

          -  Women who have irregular menstrual periods and a documented serum FSH level > 35
             mIU/mL.

          -  Women who are taking hormone replacement therapy (HRT).

        The following women are WOCBP:

          -  Women using the following methods to prevent pregnancy: Oral contraceptives, other
             hormonal contraceptives (vaginal products, skin patches, or implanted or injectable
             products), or mechanical products such as intrauterine devices or barrier methods
             (diaphragm, condoms, spermicides).

          -  Women who are practicing abstinence from intercourse from 2 weeks prior to
             administration of the 1st dose of study agent until 16 weeks after the last dose of
             study agent (Sexual inactivity by abstinence must be consistent with the preferred and
             usual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation,
             symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
             contraception)

          -  Women who have a partner who is sterile (e.g., due to vasectomy). WOCBP must be using
             an acceptable method of contraception to avoid pregnancy from the time of consent with
             <1% failure rate as stated in the product label throughout study participation, and
             for 16 weeks after the last dose of study drug in such a manner that the risk of
             pregnancy is minimized. Acceptable methods of contraception include: complete
             abstinence, any form of intra-uterine devices (without hormones), tubal sterilization
             or your partner has had a vasectomy.

        Other acceptable forms of birth control include choosing one hormonal and one barrier
        method or double-barrier methods. Barrier methods include Essure®, male or female condom,
        diaphragm with spermicide, shield, cap with spermicide, contraceptive sponge, and
        spermicidals. Hormonal methods include oral contraceptive pills, transdermal patches,
        vaginal rings, progesterone-only, and injections. Periodic abstinence (for example,
        calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not
        acceptable methods of contraception.

          -  These allowed methods of contraception are only effective when used consistently,
             correctly and in accordance with the product label. The investigator is responsible
             for ensuring subjects understand how to properly use these methods of contraception.

          -  WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity
             25 IU/L or equivalent units of HCG) within 48 hours prior to transplant (and the first
             dose of study drug intraoperatively).Women must not be breast-feeding

        Exclusion Criteria:

          -  ABO incompatible donor kidney

          -  Deceased donor <5 years of age

          -  KDPI greater than or equal to 85%

          -  HLA identical or matched kidney

          -  Transplant other than kidney: has previously received a hematopoietic stem cell/marrow
             transplant or an organ transplant other than a kidney (with the exception of corneal
             transplantation)

          -  T- and/or B-cell positive crossmatch by complement dependent cytotoxicity or flow
             cytometry against the recipient

          -  Currently on any suppressive therapy for a chronic infection (such as tuberculosis,
             pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical
             mycobacteria).

          -  Hospitalization for treatment of infection within 60 days of Day 0

          -  Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals, or
             anti parasitic agents) within 60 days of Day 0

          -  Have a history of a primary immunodeficiency

          -  Uncontrolled infection or any other unstable medical condition that could interfere
             with the study

          -  Seropositive for HIV, HCV or HBV, except for hepatitis B surface antibody positive

          -  Have a significant IgG deficiency (IgG level < 400 mg/dl) Have an IgA deficiency (IgA
             level < 10 mg/dL)

          -  Prior therapy at any time: has ever received any of the following: a) B-cell targeted
             therapy (e.g., rituximab, other anti-CD20 agents, anti-CD2 [epratuzumab], anti-CD52
             [alemtuzumab], BLyS-receptor fusion protein [BR3], TACI fragment, crystallizable (Fc),
             belimumab), or IV cyclophosphamide

          -  Live vaccines within 30 days

          -  Have a history of an anaphylactic reaction to parenteral administration of contrast
             agents, human or murine proteins or monoclonal antibodies

          -  Patients with a lymphocyte count less than 500/mm3

          -  Patients with evidence of current drug or alcohol abuse or dependence.

          -  Patients with venous access limitations likely to preclude monthly infusions

          -  Patients whom are unlikely to comply with scheduled study visits based on investigator
             judgment or has a history of substance abuse, psychiatric disorder or condition that
             may compromise communication with the investigator

          -  Myocardial infarction within 6 months prior to enrollment or New York Heart
             Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
             uncontrolled ventricular arrhythmias, or electrocardiography evidence of acute
             ischemia or active conduction system abnormalities

          -  Diagnosis of liver cirrhosis or chronic viral hepatitis

          -  Female subject is pregnant or breast-feeding. Confirmation that the subject is not
             pregnant must be established by a negative serum beta-human chorionic gonadotropin
             (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not
             required for post-menopausal or surgically sterilized women

          -  Patient has received other investigational drugs within 365 days before enrollment

          -  Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study

          -  Have evidence of serious suicide risk including any history of suicidal behavior in
             the last 6 months and/or any suicidal ideation in the last 2 months or who in the
             investigator's judgment, pose a significant suicide risk

          -  Diagnosed or treated for malignancy within 5 years of enrollment, with the exception
             of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin,
             an in situ malignancy, or low-risk prostate cancer after curative therapy.

          -  Have any other clinically significant abnormal laboratory value in the opinion of the
             investigator