Effectiveness of the Investigational Drug Campath-1H in Preventing Rejection of Transplanted Kidneys

Tolerance Induction Following Human Renal Transplantation Using Treatment With a Humanized Monoclonal Antibody Against CD52 (Campath-1H)

This protocol will test a humanized monoclonal antibody known as Campath-1H for its ability to induce a state of permanent allograft acceptance, or tolerance, when administered in combination with a brief course of the immunosuppressive drug deoxyspergualin (DSG) at the time of human renal allotransplantation. Campath-1H is specific for the common lymphocyte and monocyte antigen CD52. Its administration temporarily depletes mature lymphocytes and some monocytes without altering neutrophils or hematopoietic stem cells. Deoxyspergualin inhibits the NFkB pathway thus preventing monocyte and macrophage activation.

Recipients of living or cadaveric donor kidneys will be treated with one dose of Campath-1H prior to transplantation to insure that peripheral depletion is achieved at the time of graft reperfusion. Three subsequent doses of Campath-1H will be administered on the first, third and fifth days after the transplant to deplete passenger donor leukocytes and residual recipient cells that mobilize in response to the allograft. In addition, patients will be treated with DSG for 14 days beginning on the day prior to surgery. This trial expands on pilot studies at the NIH of 15 patients in which Campath was given alone at the time of transplantation. In those studies, excellent peripheral depletion occurred after just one dose of Campath though central depletion required additional dosing. This allowed for greatly reduced immunosuppression to be used to prevent rejection, but to date, all patients have required some immunosuppressive medication. It is hoped that the addition of DSG will eliminate the need for long-term immunosuppression.

Patients will be followed closely in the post transplant period. If patients experience rejection, they will be treated with methylprednisolone and have immunosuppression added using sirolimus as the predominant immunosuppressive agent. In the previous phase of this study without DSG, this maneuver has in all cases been successful in returning the allograft to normal function.

In addition to evaluating graft function following transplantation, this protocol will also characterize and evaluate the function of the immune system and the composition of the T cell repertoire following the administration of Campath-1H and DSG, and during immune system recovery after transplantation.

Study Overview

• Status: Completed
• Conditions: Graft Rejection; Kidney Disease
• Intervention / Treatment: Drug: Alemtuzumab and DSG

Detailed Description

This protocol will test a humanized monoclonal antibody known as Campath-1H for its ability to induce a state of permanent allograft acceptance, or tolerance, when administered in combination with a brief course of the immunosuppressive drug deoxyspergualin (DSG) at the time of human renal allotransplantation. Campath-1H is specific for the common lymphocyte and monocyte antigen CD52. Its administration temporarily depletes mature lymphocytes and some monocytes without altering neutrophils or hematopoietic stem cells. Deoxyspergualin inhibits the Rel-B/ NFkB pathway thus preventing monocyte and macrophage activation. Extensive preliminary data have been accumulated in humans using Campath-1H and its non-humanized predecessors. Additionally, data have been generated using a similar depleting scheme with and without DSG in non-human primates. Both the human and non-human primate data suggest that profound mature mononuclear cell depletion establishes a window of opportunity during which foreign tissue can be transplanted without the need for additional immunosuppression. Regulatory events occuring during mature cell repopulation in the presence of allografted tissue created a state in which the graft may not be rejected even in the absence of chronic immunosuppression.

Recipients of living or cadaveric donor kidneys will be treated with one dose of Campath-1H prior to transplantation to insure that peripheral depletion is achieved at the time of graft reperfusion. Three subsequent doses of Campath-1H will be administered on the first, third and fifth days after the transplant to deplete passenger donor leukocytes and residual recipient cells that mobilize in response to the allograft. In addition, patients will be treated with DSG 4mg/kg/d x 1 beginning on day 12 and then 2.5 mg/kg/d for an additional 13 days. This trial expands on pilot studies at the NIH of 17 patients in which Campath was dosed both prior to and after transplantation with and without DSG. In those studies, excellent peripheral depletion occured after just one dose of Campath though central depletion required additional dosing. Thus, the goal of pre-reperfusion depletion can be achieved with a single pre-operative dose but thorough depletion requires additional post-operative dosing. Lasting rejection-free survival was not realized without the addition of some, albeit reduced immunosuppression. This is thought to be due to residual post-operative monocytes that infiltrated the allograft causing modest reversible allograft dysfunction. The current dosing regimen with DSG is thus designed to accomplish both pre-operative depletion, and more thorough post operative elimination of donor and recipient cells mobilizing as a result of reperfusion, combined with therapy aimed at preventing the activation of monocytes that escape depletion. The timing of the DSG is meant to correspond with the peripheral repopulation of monocytes seen in previous patients.

Patients will be followed closely in the post transplant period for evidence of a detrimental immune response to the allograft. In the previous patients experiencing graft directed immunity the graft dysfunction was preceded by a rise in activated monocytes in the peripheral blood and augmented transcription of the cytokine Tumor Necrosis Factor-alpha (TNF-a) in the allograft. This syndrome has been resistant to treatment with the TNF-a sequestrant Infliximab and is now thought to require more comprehensive monocyte directed therapy. If patients progress and graft dysfunction occurs, patients will be treated with methylprednisolone and have immunosuppression added using sirolimus as the predominant immunosuppressive agent. This maneuver has in all cases been successful in returning the allograft to normal function. Sirolimus has been chosen since it does not act by interfering with specific T cell receptor function, and thus, provides immunosuppressive coverage during cell repopulation without interfering with the antigen specific T cell events important for tolerance induction. Non-human primate and human clinical data support both of these approaches.

In addition to evaluating graft and patient outcome following transplantation, this protocol will also characterize and evaluate the function of the immune system and the composition of the T cell repertoire following the administration of Campath-1H and DSG, and during immune system recovery after transplantation.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

Candidates for a kidney transplant performed at the Warren G. Magnuson Clinical Center.

Willingness and legal ability to give informed consent, or permission from a legal guardian.

Willingness to travel to the Clinical Center for protocol specific samples to be taken, or in some cases, the ability to send samples via overnight mail.

Availability of donor tissue for testing. This could include splenic or peripheral blood lymphocytes from a cadaveric donor or a willing living donor enrolled on the Clinic Center Living Donor Protocol who consents to periodic phlebotomy for peripheral blood lymphocyte isolation.

EXCLUSION CRITERIA:

Immunosuppressive drug therapy at the time of or 2 months prior to enrollment. Specifically, candidates must not be taking prednisone, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, antilymphocyte agents, cyclophosphamide, methotrexate, or other agents whose therapeutic effect is immunosuppressive.

Any condition that precludes serial follow-up.

Any active malignancy or any history of a hematogenous malignancy or lymphoma. Patients with primary, cutaneous basal cell or squamous cell cancers may be enrolled providing the lesions are appropriately treated prior to transplant.

Significant coagulopathy or requirement for anticoagulation therapy that would contraindicate protocol allograft biopsies.

Platelet count less than 100,000/mm(3).

Hemoglobin less than 9.0 mg/dl. Patients may be on erythropoietin therapy, but will not be placed on therapy solely to facilitate research sample acquisition.

Any known immunodeficiency syndrome.

HLA identical status with a living donor.

Any history of uncompensated cardiac insufficiency, major vascular disease, or symptomatic coronary artery disease.

Systemic or pulmonary edema.

Inability to be effectively dialyzed.

Chronic hypotension (SBP less than 100 mmHg).

Any condition that would likely increase the risk of protocol participation or confound the interpretation of the data.

CMV negative status receiving an organ from a known CMV positive donor.

EBV negative status receiving an organ from a known EBV positive donor.

Panel reactive antibody greater than 20% due to HLA antibodies.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Alemtuzumab and DSG; The recipients of live donor kidneys were treated perioperatively with alemtuzumab and DSG and followed postoperatively without maintenance immunosuppression.

Drug: Alemtuzumab and DSG; Alemtuzumab was administered intravenously at 0.3 mg/kg/dose over 3 hr. Patients received one dose on each of days -1,+1,+3 and +5 relative to transplantation (total dose 1.2 mg/kg). Methylprednisolone was given prior to each dose to limit the cytokine release: 500 mg prior to dose 1, 125 mg prior to dose 2, and 60 mg prior to doses 3 and 4. Deoxyspergualin was dosed as follows. The first two patients received 4 mg/kg as a loading dose on the day of transplant and 2.5 mg/kg daily for 13 additional days (14 days of treatment; 36.5 mg/kg total dose). The next three patients received the same dosing regimen but it was initiated on postoperative day 12 to coincide with the resurgence of monocytes on days 12- 25.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Renal Allograft Rejection	The renal allograft tolerance was evaluated clinically, by flow cytometry, and by protocol biopsies analyzed immunohistochemically and with real-time polymerase chain reaction.	from day 1 to 24 months post operation
Rejection Day of Onset	The day on which the rejection onsets.	From day 1 to 2 years post operation
Rise in Serum Creatineine Above Posttransplant Nadir		24-32 days post operation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Creatinine Level at 6 Month Post Operation		6 month post operation
Creatinine Level at Year 1 Post Operation		1 year post operation
Creatinine at 2 Years	Creatinine level of donor recepient at 2 years after transplantation	2 years post operation
Monocyte Count		4 day post operation

Collaborators and Investigators

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Publications and helpful links

General Publications

• Santiago-Delpin EA. Trends in kidney transplantation in the United States. Transplant Proc. 1998 Sep;30(6):2867-8. doi: 10.1016/s0041-1345(98)00846-x. No abstract available.

Study record dates

Study Major Dates

• Study Start: November 1, 1999
• Primary Completion (Actual): June 1, 2008
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: January 26, 2000
• First Submitted That Met QC Criteria: January 26, 2000
• First Posted (Estimate): January 27, 2000

Study Record Updates

• Last Update Posted (Estimate): October 27, 2016
• Last Update Submitted That Met QC Criteria: September 22, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Immunosuppression; Tolerance; Alemtuzumab; DSG
• Additional Relevant MeSH Terms: Urologic Diseases; Kidney Diseases; Antineoplastic Agents; Antineoplastic Agents, Immunological; Alemtuzumab
• Other Study ID Numbers: 000013; 00-DK-0013