Clinical Trial Result Information

Protocol number
M39037

Title of Study
A phase II, multicenter, open-label trial on the efficacy and safety of Rituximab therapy in patients with B-cell post-transplant lymphoproliferative disorders (B-PTLD) (organ or bone marrow transplant recipients) with progressive disease after immunosuppressive therapy reduction or discontinuation.

Sponsor
Roche SAS

Company division
Pharmaceutical

Product name
MabThera/Rituxan

Generic name
rituximab

Therapeutic area
Lymphomas

Clinical study summary
This was an open-label, non-randomized (single treatment arm), multicenter study to evaluate the anti-tumor efficacy and safety of MabThera monotherapy in patients with B-cell post-transplant lymphoproliferative disorders, with progressive disease after immunosuppressive therapy. Patients with no change or with a complete or partial response were to be monitored until disease progression, for a maximum of 12 months. All patients with disease progression were withdrawn from the study.

Study center(s)
19 centers in Belgium and France.

Phase of development
II

Objectives
Primary: To evaluate the anti-tumor efficacy of MabThera monotherapy on the objective response rate (Complete Response or Unconfirmed Complete Response or Partial Response) at Day 80 ± 7 days, in patients with B-cell post-transplant lymphoproliferative disorders (B-PTLD) with progressive disease after immunosuppressive therapy reduction or discontinuation.
Secondary: To evaluate the anti-tumor efficacy at 6 months and 12 months (Survival at M6 and M12, Event-Free Survival at M6 and M12, Disease-Free Survival at M6 and M12, Progression-Free Survival at M6 and M12, Response duration at M6 and M12); to evaluate the safety profile of MabThera monotherapy throughout the study period; to evaluate the effect of MabThera on the transplant.

Methodology
Eligible patients received weekly infusions of MabThera 375mg/m² for 4 weeks. To prevent allergic events, premedication with an analgesic and an antihistamine was also given 1-2 hours before each MabThera infusion. Anti-tumor efficacy was assessed on day 80 +/- 7, and at months 6 and 12. Patients with disease progression were withdrawn from the study.

Number of patients (planned/analyzed)
57 patients enrolled

Diagnosis and main criteria for inclusion
Patients aged between 1 and 75 years, with onset of a B-cell lymphoproliferative disorder occurring after an organ transplant (SOT) or hematopoietic stem cell transplant (HSCT).

Test product, dose and mode of administration or test procedure
MabThera 375mg/m², one infusion per week given over a mean duration of at least four hours. The infusion was repeated weekly for four weeks, i.e., the treatment consisted of a total of four infusions.

Duration of treatment
4 weeks

Reference therapy, dose and mode of administration or reference procedure
N/A.

Criteria for evaluation (efficacy, safety)
Primary: Anti-tumor efficacy (objective response) on D80 ± 7 days evaluated as a success or failure. For patients with measurable mass, success was defined as a Complete Response or Unconfirmed Complete Response or Partial Response on D80 ± 7 days. For patients without measurable mass, Complete Response was defined by disappearance of all clinical symptoms and/or biological abnormalities present at inclusion (including abnormal viral load) and disappearance of blood and medullar infiltration.
Secondary: Safety: Number of patients with at least one treatment-related adverse event during MabThera therapy. Antitumor efficacy: Survival at M6 and M12, Event-Free Survival, Disease-Free Survival, Progression-Free Survival and Response Duration up to M6 and M12. Transplant Survival: Number of patients with one or more episode of transplant rejection.

Statistical methods
Based on preliminary data, the working hypothesis was a 70% total response rate on D80. Under this hypothesis, inclusion of 37 patients was required for the Fleming single-stage Phase II procedure with π₀=0.5 and π₂=0.7. The type I error (probability of rejecting the hypothesis π≤π₀ when it is, in fact, true) was set at α = 5% (one side).The Type II error (probability of rejecting the hypothesis π≥π₂ when it is, in fact, true) was set at β = 20%. The number of patients outside the Per-Protocol population was estimated at about 15%. Consequently, a total of 45 patients were to be included in the study.

Summary (efficacy, safety, other results)
Efficacy: Efficacy analyses were performed on the per protocol population, i.e. on 55 patients. Forty three patients (78%) received the 4 planned infusions. Twelve patients (22%) received less than 4 infusions due to withdrawal before the D22 visit (death or retreatment).
Primary: At D80±7, 25 patients (45.5%) were classified as ‘success’ with a 95% confidence interval at [32; 59]: 15 CR, 3 CRu and 7 PR were observed.
The only factor predictive of response at D80 was a normal LDH level using univariate logistic regression analysis (p=0.047) (odds ratio = 3.6). The probability of responding to treatment was 3.6 times higher for patients with LDH ‘normal‘ compared to patients with LDH ‘abnormal’.
Secondary: Response duration was evaluated on 25 patients who had responded at D80. Response duration was defined as the time between response and relapse (progression). Four patients (3 PR and 1 CR) relapsed after D80: first relapse was observed 15 days after response and last relapse 173 days (6 months) after response. The response rate at 6 and 12 months without progression was estimated at 83.4% (se=0.076).
The progression free survival rates at 6 months and 12 months were estimated with the Kaplan–Meier method as 47.8% (se=0.070) and 43.7% (se=0.070) respectively.
Among the 55 eligible per protocol population patients, 25 patients (45.45%) died. The overall survival rate estimated with the Kaplan-Meier method was 76% (se=0.057) at 6 months and 63 % at 12 months (se=0.066). The only factor significantly predictive of survival was the ECOG score (p=0.0012), with a risk of death 3.4 times higher in the score 3 group compared to the score 0 to 2 group.
In the HSCT population, the mean EBV load was 20605.90±26328.49 copies/µg DNA at D0 and 9.25±8.50 copies/µg DNA at D80. In the SOT population, the mean EBV load was 18929.03±76949.64 copies/µg DNA at D0 and 1031.23±4270.44 copies/µg DNA at D80.
Regarding graft rejection among the 44 SOT patients, 9 patients (20.5%) developed at least one episode of rejection (acute or chronic): heart for 4 patients, kidney for 3 patients, liver for 1 patient and lung for 1 patient. Except for one case which occurred on D27, these rejections occurred more than 5 months after the start of rituximab treatment. One rejection was fatal, one year after treatment completion. The rate of patients without rejection was evaluated as 87.2% at 6 months (se=0.064) and 52.5% at 12 months (se=0.135).

Safety: Safety was analyzed in 57 eligible patients (i.e. who received at least one infusion of MabThera).
During the period D1-D50 (28 days after the last administration), the most common AEs (i.e. occurring in more than 10 % of patients) were: abdominal pain (17.5%), chills (12.3%), anemia (12.3%), fever (10.5%), vomiting (10.5%). Three adverse events led to treatment discontinuation and death in 3 patients (aggravation of neurological disorders, acute dyspnea with probable bronchospasm, septic shock).
During the period from D51 to the end of trial, AEs occurring in more than 5 % of patients were: abnormal renal function (9%), graft rejection (9%), abdominal pain (9%), dyspnea (9%), graft versus host disease (7%) and fever (7%).
One hundred grade 3/4 adverse events were reported in 37 patients (65%), 55 between D1 and D50, and 45 events after D50 and to the end of the trial. Only one (aggravated hypertension) was reported as related to treatment.
A total of 73 serious adverse events were reported, including 2 events reported as related to treatment (but causal relationship difficult to assess): intestinal perforation with peritonitis, purpura with myalgia.
Three cases of neutropenia were reported after MabThera completion, the cause of one of which could not be explained. In this case, neutropenia was asymptomatic and spontaneously resolved.
Twenty six deaths were reported during the study. The most frequent cause of death was progression of lymphoma (57.7%). Four deaths related to infection were reported.

Conclusions
This trial conducted in adult patients and children showed that MabThera monotherapy was effective in treating B cell post transplant lymphoproliferative disorders (organ transplant or hematopietic stem cell transplant) achieving a 45% overall response rate with a low rate of relapse at 1 year (response rate without progression 83.4% at 12 months). In this population, the treatment was well tolerated without significant adverse impact on transplant.

Publications (references, if available)
Choquet S et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders : results of a prospective multicenter Phase 2 study. Blood 2006; 107(8): 3053-7

Date of report
2/1/2007