Roche trials database

Protocol number:

PA16215

Title of Study:

Immune response to neoantigen and recall antigen in pediatric renal transplant recipients treated with the IL-2Rα monoclonal antibody, daclizumab (Zenapax).

Sponsor:

Hoffmann-La Roche Inc

Company division:

Pharmaceutical

Product name:

Zenapax

Generic name:

daclizumab

Therapeutic area:

• Kidney Transplantation

Clinical study summary:

This was a prospective, open label, multicenter study to determine whether pediatric renal transplant patients were able to mount a primary immune response, while treated with Zenapax. The study was not fully recruited, and only a small number of patients contributed to the analysis.

Study center(s):

Four centers in the USA.

Phase of development:

IV

Objectives:

To evaluate whether the use of humanized anti-IL-2Rα monoclonal antibody Zenapax (daclizumab) impairs the ability of pediatric renal transplant recipients to elicit a primary immune response.

Methodology:

Patients who met the eligibility criteria were enrolled into the appropriate groups. All patients were receiving (Group A, experimental) or had received (Group B, control) Zenapax in addition to the maintenance immunosuppression regimen of calcineurin inhibitor, mycophenolate mofetil and corticosteroids.
On days 1 and 29, patients received DT vaccine intramuscularly and KLH vaccine intradermally. Blood was drawn on days 1, 22, 29, 43 and 57 to detect anti-tetanus toxoid (TT) IgG, anti-KLH IgM and anti-KLH IgG. Blood was drawn on day 168 to detect anti-KLH IgG and anti-TT IgG levels. Blood was drawn on days 1, 22, 29, 43 and 57 to evaluate KLH and TT cellular responses by BrdU.
Patients who did not demonstrate significant humoral and/or cellular responses to KLH were rechallenged 6 months after the second vaccination with a second increased dose KLH vaccination course. Patients with humoral but no cellular responses to DT vaccinations were rechallenged 6 months after the second vaccination with a second two-dose DT vaccination course. Non-responders received the second two-dose vaccine course on days 196 and 224.
Delayed type hypersensitivity (DTH) responses were assessed 48 hours after each KLH vaccine administration.
Safety follow-ups, CD25+ percentages and humoral responses were assessed at month 6 for all patients and at month 12 for rechallenged patients.

Number of patients (planned/analyzed):

82 patients planned / 11 patients enrolled

Diagnosis and main criteria for inclusion:

Pediatric renal transplant recipients who were receiving or had received five doses of Zenapax as part of their immunosuppressive regimen.

Test product, dose and mode of administration or test procedure:

 Keyhole Limpet Hemocyamin (KLH): Initial challenge (all patients).
Patients 2 to <12 years: 250μg on days 1 and 29.
Patients 12 to 19 years: 500μg on days 1 and 29.
Rechallenge (for patients who met the criteria for rechallenge)
Patients 2 to <12 years: 250μg or 500μg (if enrolled after protocol amendment) on days 196 and 224.
Patients 12 to 19 years: 500μg or 750μg (if enrolled after protocol amendment) on days 196 and 224.
KLH was administered by intradermal injection.

Diptheria and Tetanus Toxoid (DT)
0.1mL dose of a 1:3 dilution of DT on days 1 and 29 and (if the criteria for rechallenge were met) on days 196 and 224.
DT was administered by intramuscular injection.

Zenapax (daclizumab)
Full course of five doses (1mg/kg within 24 hours pre-transplant the 1mg/kg every other week for 4 doses).
Group A: patients were receiving a full course of Zenapax therapy. Day 1 vaccines were administered immediately prior to the fifth dose of Zenapax.
Group B: patients had completed a full course of Zenapax therapy in the previous 4-18 months.

Duration of treatment:

4 weeks for responders, and 32 weeks for non-responders.

Reference therapy, dose and mode of administration or reference procedure:

N/A

Criteria for evaluation (efficacy, safety):

Efficacy: All patients had their tetanus and KLH antibodies evaluated at screening and on days 1, 22, 29, 43, 57 and 168.
Patients also had their cellular responses to tetanus and KLH antigens detected on days 1, 22, 29, 43 and 57.
Safety: Clinical assessments, incidence of adverse events including opportunistic infections, concomitant medications, laboratory abnormalities, rejections, patient and graft survival, and malignancies were collected.

Statistical methods:

For the primary variable, the proportion of patients who developed a positive antibody response to KLH immunization after the second KLH vaccination was to be compared between the two groups.
Secondary variables and safety parameters were summarized descriptively.
For patients rechallenged 6 months later, the variables measured in the primary portion of the study were to be summarized, where applicable. 

Summary (efficacy, safety, other results):

Efficacy: Two of the five Group B (control) patients had humoral responses to KLH and four had cellular responses to KLH by day 57 after the initial course of vaccines. Of the five Group A (experimental) patients who were evaluable for KLH humoral response, two demonstrated increases in KLH IgG that met the response definition. Most of the KLH cellular responses in Group A were not evaluable but of the two patients who had an evaluable response, one attained a cellular response to KLH by day 57. From both groups, 4 patients who did not respond (humoral/cellular) to the initial vaccine course were rechallenged with a second two-dose course of KLH. Two of these patients (one in each group) mounted a humoral response after rechallenge. Time to peak response was variable.
After the initial vaccination course, three of four group B patients evaluable for tetanus humoral response demonstrated increases in tetanus IgG that met the response definition. The same proportion of evaluable Group B patients also met the cellular tetanus response definition. Of the five Group A patients evaluable for tetanus humoral responses, three met the tetanus humoral response definition. Three Group A patients were evaluable for tetanus cellular responses. Of these, two patients demonstrated increases in lymphocyte proliferation response (LPR) that met the response definition. All patients maintained protective tetanus titers.

Safety: Ten of the 11 patients experienced at least one adverse event, the majority of which were of mild or moderate intensity, with infections and gastrointestinal disorders being the most common adverse events. Five patients experienced a serious adverse event (BK virus infection, Epstein-Barr virus [EBV] infection, hematuria, gastroenteritis and viral infection). The event of EBV infection in a patient in Group A was severe in intensity, was considered by the investigator to be related to study drug (Zenapax), and led to withdrawal of the patient from the study. One patient in Group A experienced two (non-serious) opportunistic infections: systemic cytomegalovirus infection and oral candidiasis.

Conclusions:

There were no significant safety concerns in this study and no evidence of tolerance. The data showed that pediatric patients were able to mount some type of immune response regardless of the timing of their Zenapax administration, and that even in the presence of maximally suppressed CD25+ cells, immune responses were not completely inhibited. However it should be noted that this study was not fully recruited and the number of patients who contributed to this analysis was small.

Date of report:

04.06.2007

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