Belatacept Post Depletional Repopulation to Facilitate Tolerance

Acute rejection is a common problem after a kidney transplant. Rejection can occur when the kidney recipient's immune system tries to attack (or reject) the new kidney. Rejection typically most often develops in the first few months after a transplant.

This single center study will seek to determine if a new combination of anti-rejection medications, including the recently FDA approved drug called Belatacept, is better than the current standard anti-rejection drug regimen at preventing rejection. Also to be determined will be whether the new combination of drugs will allow participants to wean off their oral anti-rejection medications over time.

This study will test the safety and effectiveness of a new investigational drug combination using alemtuzumab, belatacept, and sirolimus when given with or without donor bone marrow.

This combination of medicines has not been tested before in humans. Alemtuzumab (Campath) is approved for use in some types of white blood cell cancers, but is considered investigational in transplant patients. Belatacept is now FDA approved and is being studied in transplant patients. Sirolimus (Rapamune) is approved for use in transplant patients, but its use with belatacept and alemtuzumab is investigational.

In the initial 20 subjects enrolled in the study, half tested whether an infusion of bone marrow from the kidney donor would improve the effect of these drugs. This bone marrow infusion was also considered investigational.

Enrollment of 20 additional subjects was begun in January, 2013. The donor bone marrow infusion has been eliminated. Enrollment is open to primary living and deceased donor kidney recipients.

This study will be a single-center, open-label,proof of concept study in non-HLA-identical living and deceased donor renal transplants. The initial 20 subjects were randomized to either receive/not to receive a single donor bone marrow infusion in addition to the investigational combination of alemtuzumab, belatacept, and sirolimus. Since the bone marrow infusion has been eliminated in the second group of 20 subjects, no randomization will be required. All recipients in the second group of 20 subjects will receive the same investigational combination of alemtuzumab, belatacept, and sirolimus.

At the time of transplant, participants will receive a 3-hour IV infusion of 30 mg. of alemtuzumab. Participants will receive a combination of sirolimus and belatacept for at least 1 year. At that time, eligible participants will consent to and begin oral immunosuppressive withdrawal or continue therapy through study close. Sirolimus will first be weaned by halving the dose and/or increasing the dosing interval over at least a 2-6 month period. After sirolimus is discontinued, participants will remain on monthly IV belatacept monotherapy indefinitely.

Follow-up will continue for at least five years. If subjects are successfully weaned from oral immunosuppression during their participation in this trial, no other alternative therapy will be warranted. Since belatacept is now FDA approved, subjects will be eligible to continue this therapy after their study participation has ended.

• Drug: Belatacept
  Belatacept will be given as an IV infusion of 10mg /kg over 30 minutes. This will be repeated on study days 4 and 8 (prior to bone marrow infusion in the first group of subjects) and 15 then every 2 weeks for 5 additional doses. After week 24, belatacept will be given at a dose of 5 mg/kg once every 4 weeks indefinitely.
  Other Names:

  • LEA29Y
  • Nulojix
• Drug: Belatacept
  Belatacept will be given as an IV infusion at 10mg/kg over 30 minutes on the day of transplantation. This dose will be repeated on study days 4, 8, and 15, then every 2 weeks for 5 additional doses. After week 24, belatacept will be given as an infusion of 5 mg/kg once every 4 weeks indefinitely.
  Other Names:

  • LEA29Y
  • Nulojix
• Drug: Alemtuzumab
  All patients will receive a single dose of 30 mgs. on the day of transplantation.
  Other Name: CAMPATH
• Other: donor bone marrow

  The bone marrow was given as an IV infusion over 3 hours on postoperative day 7 (study day 8) in the initial group of 20 randomized subjects. The formulated dose was 1 x 10(8th power) unfractionated nucleated cells/kg recipient ideal body weight.

  A proposed total of forty patients will be enrolled in this study. Enrollment was reopened last year to include 20 additional living or deceased donor kidney recipients.

  Half of the first 20 recipients were randomized to receive a single donor bone marrow infusion. Half did not receive the infusion. Donor bone marrow infusion in the second group of 20 subjects has been eliminated.

• Experimental: 1

  All patients will be given a single dose of alemtuzumab on the day of transplantation. All patients will receive belatacept and sirolimus for 1 year.

  Ten patients in the first group of 20 subjects received a single dose of donor bone marrow 7 days after transplantation.

  At the time of transplant, all patients will receive a single dose of 500 mg of methylprednisolone IV over 30 minutes followed within 1 hour by an IV infusion of 30 mg. of alemtuzumab over 3 hours.

  Interventions:

  • Drug: Belatacept
  • Drug: Alemtuzumab
  • Other: donor bone marrow
• Experimental: 2

  All patients will be given a single dose of alemtuzumab on the day of transplantation. All patients will receive belatacept and sirolimus for one year.

  Half of the initial 20 subjects did not receive an infusion of donor bone marrow. None of the additional 20 subjects in the second group will receive donor bone marrow.

  At the time of transplant, all patients will receive a single dose of 500 mg of methylprednisolone IV over 30 minutes, followed within 1 hour by an IV infusion of 30 mg of alemtuzumab over 3 hours.

  Interventions:

  • Drug: Belatacept
  • Drug: Alemtuzumab

Inclusion Criteria:

• Recipients age 18 or older of an HLA-non-identical,living or deceased donor kidney transplant.
• A willing renal donor who consents for subsequent donation of donor blood for testing throughout the follow-up period and for use of his/her kidney in this experimental study.

Exclusion Criteria:

• Immunosuppressive drug therapy within 1 year prior to enrollment.
• Active malignancy or history of malignancy within 5 years of enrollment.
• Any history of blood malignancy or lymphoma.
• Any known immunodeficiency syndrome, including HIV infection.
• Absence of EBV or CMV specific antibodies in cases with evidence of EBV and/or CMV infection.
• Women of child-bearing potential unwilling or unable to use an acceptable method of birth control.
• Women who are pregnant or breastfeeding at the time of enrollment or study drug administration.
• Donor age <18 years.
• Subjects with protocol-specific etiologies of underlying renal disease.
• Subjects with a positive T-cell lymphocytic crossmatch or historical evidence of donor specific alloantibody by solid phase or flow-based detection methods.
• Prior solid organ transplant or potential to require a concurrent organ or cell transplant.
• Positive Hepatitis B or C antibodies and PCR positive for the same.
• Active (tuberculosis) TB requiring treatment within the previous 3 years.
• Known positive PPD unless chest x-ray is negative or treatment for latent TB has been completed.
• Active infection or other contraindications.
• History of drug or alcohol abuse within the past 5 years.
• Psychotic disorders which would interfere with adequate study follow-up.
• Active peptic ulcer disease, chronic diarrhea, or gastric malabsorption.
• All women 40 years or older with first degree family history of breast cancer will be required to have a screening mammogram within 6 months of study enrollment.
• Subjects with suspicion of breast malignancy which cannot be ruled out will be excluded.
• Belatacept use within 30 days prior to the day 1 visit.
• Prisoners or individuals who are involuntarily incarcerated.

• Bristol-Myers Squibb
• FDA Office of Orphan Products Development