CAMPath and BELimumab for Transplant Tolerance in Sensitized Kidney Transplant Recipients

CAMPath and BELimumab for the Induction of Donor Specific Humoral Transplant Tolerance in Sensitized Kidney Transplant Recipients To Improve Long-Term Allograft Survival

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.

Accrual Objective: 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.

Study Design: This is an open-label pilot-study to evaluate the safety and efficacy of belimumab plus standard of care in the prevention of de novo donor specific antibody in adult subjects after kidney transplantation.

The investigators will enroll 5 adult, deceased or living donor kidney transplant recipients who are sensitized, evidenced by: Positive sum Donor Specific Antibody (DSA)<1000 MFI and/or Panel of Reactive Antibodies (PRA)>0%. The primary endpoint of this study is de novo DSA production. There are two main reasons for selecting this patient population for the proposed study. 1) Sensitized patients are known to have higher rates of de novo DSA production and 2) Patients with low levels of DSA (sum DSA<1000 MFI) will enable more fidelity in determining the DSA that is produced de novo.

Kidney transplant recipients will receive the standard of care (alemtuzumab and steroid induction with mycophenolic acid and tacrolimus maintenance immunosuppression), plus six months of therapy with belimumab. Belimumab 10 mg/kg will be administered IV for 6 months at the following intervals: Day of transplant (Day 0), and then at Weeks 2, 4, 8, 12, 16, and 20 post-transplant.

Study Duration: Subjects will be treated for 6 months with belimumab and followed for DSA production for 1 year.

Primary Study Objectives: In this proposal the investigators plan to determine (a) whether the addition of belimumab to the standard of care (SOC: alemtuzumab and steroid induction with mycophenolic acid and tacrolimus maintenance immunosuppression) is safe and effective in preventing de novo DSA production at 1, 3, 6, 9, and 12 months post-transplant.

Secondary efficacy endpoints will be 1) graft survival and function as determined by serum creatinine/eGFR and urine protein at 1, 3, 6, 9, and 12 months 2) rates of acute cellular and antibody mediated rejection, at 1, 3, 6, 9, and 12 months.

Primary Outcomes: To determine whether the addition of belimumab to the standard of care (SOC: alemtuzumab and steroid induction with mycophenolic acid and tacrolimus maintenance immunosuppression) is safe and effective in preventing de novo DSA production 1, 3, 6, 9, and 12 months.

Secondary Outcomes: Secondary endpoints will be 1) graft survival and function as determined by serum creatinine/eGFR and urine protein at 1, 3, 6, 9, and 12 months 2) rates of acute cellular and antibody mediated rejection at 1, 3, 6, 9, and 12 months and 3) the nature, frequency, and severity of serious and non-serious adverse events ≥Grade 2 per Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0.

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