Clinical Trial Result Information

Protocol number
M39005

Title of Study
Treatment of follicular and mantle cell non-Hodgkin’s lymphoma with anti-CD20 antibody rituximab (IDEC-C2B8) after high-dose chemotherapy with autologous CD34+ enriched peripheral blood stem-cell transplantation.

Sponsor
Hoffmann-La Roche AG

Company division
Pharmaceutical

Product name
MabThera/Rituxan

Generic name
rituximab

Therapeutic area
Non-Hodgkin’s Lymphoma

Clinical study summary
This open-label, single-arm, multicenter, phase II study evaluated the efficacy and tolerability of rituximab (MabThera) following high-dose chemo- and radiation therapy and autologous peripheral blood stem-cell transplantation (ASCT) in patients with advanced low-grade malignant lymphomas. Patients were given MabThera 375 mg/m2 weekly for 4 weeks approximately 8 weeks after CD34+ cell enriched ASCT.

Study center(s)
5 centers in Germany.

Phase of development
II

Objectives
Primary: To evaluate the progression-free survival at 2 years after transplantation. Secondary: (1) Duration of remission; (2) Efficacy of B-cell depletion; (3) Immunologic recovery; (4) Overall survival after 2 years of follow-up; (5) Toxicity of MabThera (adverse events, laboratory tests, vital signs, number of infections).

Methodology
Patients with complete response or partial response after induction chemotherapy were included in the study, and received high-dose TBI/Cy radiochemotherapy followed by autologous peripheral blood stem-cell transplantation. After hematological recovery, but not earlier than 8 weeks, the patients received 4 applications of study medication in weekly intervals. Until tumor progression, stagings were foreseen every 3 months in the first year after transplantation, and every 6 months thereafter. Follow-up for all patients was performed until death or study closure.

Number of patients (planned/analyzed)
30 enrolled; 29 in ITT analysis.

Diagnosis and main criteria for inclusion
Male and female patients 18 to 60 years of age with newly diagnosed follicular (FL) or newly diagnosed or relapsed mantle cell lymphoma (MCL) at advanced stages III-IV according to Ann-Arbor criteria; t(14;18) or t(11;14) or monoclonal immunoglobulin rearrangement.

Test product, dose and mode of administration or test procedure
MabThera vials of 500 mg and 100 mg. The antibody was given at 375 mg/m2 by slow IV infusion.

Duration of treatment
4 weeks.

Reference therapy, dose and mode of administration or reference procedure
None.

Criteria for evaluation (efficacy, safety)
(1) Patients’ bone marrow (BM) and/or peripheral blood (PB) samples were monitored serially for minimal residual disease (MRD); (2) Responses were evaluated by CT scan, and Cheson criteria were used for response definition. Radiology reports gave objective measurement of indicator lesions at each participating site. Patients with bone marrow involvement at study entry had to repeat bone marrow aspiration and (3) biopsy to confirm complete response (CR); (4) Event-free survival (EFS) or time to treatment-failure (TTF); (5) Toxicity according to the National Cancer Institute of Canada Common Toxicity Criteria.

Statistical methods
Data for 30 patients were considered sufficient to allow meaningful descriptive analyses in order to determine the study objectives. If a patient had received at least 1 MabThera infusion, this patient was considered eligible for the intention-to-treat (ITT) analysis. Response rates were analyzed by frequency tables. EFS and overall survival (OS) were analyzed by the Kaplan-Meier method. Patients without progression or death were censored at the last information available showing that the patient had not yet progressed.

Summary (efficacy, safety, other results)
Consolidation with MabThera started a median of 61.5 days after transplantation (range: 38-108 days). Twenty-eight patients received 4 applications in weekly intervals. In error, 1 patient received only the first 2 applications. Due to rounding, the average applied dosage was slightly below the recommended dose of 375 mg/m2. In 2 patients, the infusion rate had to be reduced due to adverse events during the first application. After MabThera consolidation, late responses were seen and 28 patients (96.6%, 95% CI: 82.2%-99.9%) were evaluated as having complete response (CR) 24 months after transplantation. One patient only reached partial response (PR) and developed progressive disease after 24 months.
Until study closure, progressive disease was observed in 6 patients (2 FL and 4 MCL patients) and 1 patient died unexpectedly in CR.

The progression-free survival (PFS) rates after a median observation time of 53 months following transplantation were 93% (95% CI: 75%-98%) for the 2-year PFS and 75% (95% CI: 54%-87%) for the 5-year PFS, but survival rate estimates were different for FL and MCL patients. Five-year PFS was 90% (95% CI: 66%-97%) in FL patients and only 31% (95% CI: 10%-69%) for MCL patients. Kaplan-Meier plots show a significant difference between these patient groups as indicated by the log-rank test (P = 0.0064). Whereas the median was not reached in FL patients, median PFS was 48 months in MCL patients.

Similar differences were obtained for time to progression and duration of remission. Median overall survival (OS) was not reached in both groups as only 2 patients died (both in the MCL group). Overall survival rates after transplantation were estimated to be 97% for the 2-year OS and 93% for the 5-year OS. In MCL patients the 2-year OS was estimated to be 89% (95% CI: 43%-98%) and the 5-year OS was estimated to be 77% (34%-94%). All the FL patients were alive at study closure accounting for a 2-year and 5-year OS of 100%. CD20 depletion was effective immediately after 4 applications of MabThera, recovering about 18 months after transplantation. Immunoglobulin levels were low during the whole observation period.

Only 1 patient was excluded from standard analyses and results agree with the ITT analysis.
Evaluation of MRD was performed in 26 patients, as no molecular marker was detected prior to study start in 3 patients. Before high-dose radiochemotherapy, 18% of the patients tested negative. After 4 applications of MabThera, 68% were negative, and at 6 months after transplantation, 100% of the patients were negative, indicating a high molecular remission rate. During follow-up, some patients transiently tested positive and negative again thereafter while presenting CR clinically. Also, clinical relapse was observed in patients who tested PCR- negative.

During the study, a total of 173 treatment-related adverse events were observed. Forty-two percent were grade 1, 42% grade 2, 11% grade 3, and 5% grade 4. Infections accounted for 38% of all treatment-related adverse events and affected 83% of all patients. Most infections were mild or moderate and only 8 grade 3 and no grade 4 infections were reported. Only 9 treatment-related adverse events were grade 4, and 5 of them were severe lymphopenia. Other grade 4 adverse events were 1 case of leucopenia, 1 case of neutropenia, 1 case of thrombopenia, and 1 unexpected death due to respiratory failure. A total of 17 serious adverse events were reported, but 3 occurred prior to MabThera treatment and 3 were reported more than 1 year after MabThera treatment.

Conclusions
The study demonstrated that MabThera consolidation following high-dose radiochemotherapy and ASCT was safe, and led to high rates of durable remissions.

Publications (references, if available)
Brugger W, Hirsch J, Grünebach F, et al. Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: a prospective, multicenter phase II study. Ann Oncol 2004;15:1691-1698.

Date of report
2/24/2005