Clinical Trial Result Information

Protocol number
M39045

Title of Study
A randomized intergroup trial of first-line treatment for patients with diffuse large B-cell lymphoma (DLBCL) with a CHOP-like chemotherapy regimen with or without the anti-CD20 antibody rituximab.

Sponsor
F. Hoffmann-La Roche Ltd

Company division
Pharmaceutical

Product name
MabThera/Rituxan

Generic name
rituximab

Therapeutic area
Non-Hodgkin’s Lymphoma

Clinical study summary
This was a randomized, open-label, inter-group, multi-center, prospective, controlled clinical trial investigating the effect of adding MabThera (rituximab) to a CHOP-like chemotherapy regimen in patients with diffuse large B-cell non-Hodgkin’s lymphoma.

Study center(s)
A total of 172 centers in Argentina, Australia, Austria, Brazil, Canada, Czech Republic, Denmark, Finland, France, Germany, Israel, Italy, Norway, Poland, Spain, Sweden, Switzerland and UK.

Phase of development
III

Objectives
To investigate the efficacy and tolerability of MabThera (rituximab) in combination with a CHOP-like chemotherapy regimen in patients with CD20-positive, diffuse large B-cell non-Hodgkin’s lymphoma with low risk disease according to the IPI (IPI 01).

Methodology
Patients were randomly assigned to receive CHOP-like chemotherapy with or without MabThera (R-CHEMO vs CHEMO). Patients with bulky disease at baseline received additional involved-field radiotherapy to these areas (30-40 Gy) at the end of induction treatment. In addition, radiotherapy to areas of extranodal involvement was given at the discretion of the treating physician. If radiotherapy was to be given, this had to be decided at study entry (prior to randomization) and documented at baseline.

Number of patients (planned/analyzed)
824 patients were recruited

Diagnosis and main criteria for inclusion
Patients 18 to 60 years of age with CD20-positive, diffuse large B-cell lymphoma and low risk disease (IPI 01) and stage II-IV disease or bulky stage I disease.

Test product, dose and mode of administration or test procedure
MabThera 375 mg/m² i.v. on day 1 of each cycle/ 6 cycles in combination with CHOP and CHOEP, on day 1, 22, 43, 64, 85 and 106 in combination with MACOP-B, and on day 1 (cycles 1 and 4), on day 8 (cycles 2 and 5) and in the first and fourth week after cycle 6 in combination with PMitCEBO.

Duration of treatment
6 x 2 week or 6 x 3 week cycles of treatment

Reference therapy, dose and mode of administration or reference procedure
CHOP-like chemotherapy: CHOP-21, CHOEP-21, MACOP-B or PMitCEBO. (i.e. standard chemotherapy regimen of the respective cooperative lymphoma study groups).

CHOP-21 (cycles repeated at 21 day intervals, 6 cycles in total):
Cyclophosphamide 750 mg/m² i.v. on day 1
Doxorubicin 50 mg/m² i.v. on day 1
Vincristine 2 mg (abs.) i.v. on day 1 or 1.4 mg/m² (max. 2 mg) i.v. on day 1 (for sites from the UK)
Prednisone 100 mg/d p.o. on days 1-5

CHOEP-21 (cycles repeated at 21 day intervals, 6 cycles in total):
CHOP chemotherapy (see above) plus
Etoposide 100 mg/m² i.v. on days 1-3 or 100 mg/m² i.v. on day 1 and 200 mg/m² p.o. on days 2-3 (for sites from Sweden).

MACOP-B:
Cyclophosphamide 350 mg/m² i.v. on day 1, 15, 29, 43, 57 and 71
Doxorubicin 50 mg/m² i.v. on day 1, 15, 29, 43, 57 and 71
Methotrexate 400 mg/m² i.v. on day 8, 36 and 64
Vincristine 1.4 mg/m² i.v. on day 8, 22, 36, 50, 64 and 78
Bleomycin 10mg/m² on day 22, 50 and 78
Prednisone 40 mg/m² p.o. or i.m. on days 1-84

PMitCEBO (cycles repeated at 14 day intervals, 6 cycles in total):
Mitoxantrone 7 mg/m² i.v. on day 1
Cyclophosphamide 300 mg/m² i.v. on day 1
Etoposide 150mg/m² on day 1
Vincristine 1.4mg/m² (max. 2 mg) i.v. on day 8
Bleomycin 10 mg/m² i.v. (bolus) on day 8
Prednisolone 50 mg/d p.o. week 1-4 then 50 mg alt week 5 to treatment end
Cotrimoxazole 480 mg bd 3 times weekly in weeks 1-2 after treatment end. Recycle day 15.

Criteria for evaluation (efficacy, safety)
Efficacy: Primary: Time to treatment failure (TTF). Secondary: CR rate; overall survival. Safety: Safety endpoints comprised of laboratory tests, adverse events (AEs) and serious adverse events (SAEs).

Statistical methods
The primary endpoint TTF was analyzed using the log rank test. A Cox proportional hazard model was used to calculate the hazard ratios and 95% confidence intervals. Complete remission and progression rates were presented with the 95% confidence intervals. Overall survival was assessed analogous to the primary endpoint TTF.

Summary (efficacy, safety, other results)
Efficacy: The addition of MabThera to a CHOP-like chemotherapy regimen significantly prolonged TTF and OS in the full analysis population. Additionally, significantly more patients in the R-CHEMO arm than in the CHEMO arm achieved a (confirmed or unconfirmed) complete response.

	CHEMO	R-CHEMO	Hazard ratio	p-value (log rank test)
TTF (years)	ne	3.7	0.45	<0.0001
OS (years)	ne	ne	0.40	0.0002
CR or CRu (%)	67.2	84.9	na	<0.0001*

* Chi square test; ne = not estimable; na=not available

Exploratory analyses of both parameters, TTF and OS, were performed in a number of subgroups. The addition of rituximab to a CHOP-like chemotherapy regimen had a beneficial effect on TTF and OS in all subgroups of patients analyzed.

Safety: Over 90% of the patients in both treatment arms received 6 cycles of treatment regardless of the treatment regimen (i.e. 2-weekly or 3-weekly chemotherapy regimen).
The overall tolerability of treatment was not significantly affected by the addition of MabThera to CHOP-like chemotherapy. Adverse events/toxicities, grade 3/4 adverse events and serious adverse events (SAEs) were evenly distributed with only slight imbalances between the two treatment arms.
Overall, 41% of patients in the R-CHEMO arm and 37% of patients in the CHEMO arm reported at least one grade 3/4 AE. In both treatment groups, hematological disorders, gastrointestinal disorders and infections/infestations were the most common type of grade 3/4 AEs. The AEs were generally well balanced between the two treatment arms. There was a higher incidence of grade 3/4 cardiac events in the R-CHEMO arm than in the CHEMO alone arm (11 events in 10 patients on R-CHEMO versus 5 events in 5 patients on CHEMO). Out of these, 6 events (in 6 patients) in the R-CHEMO arm and 1 event (in 1 patient) in the CHEMO arm were considered to be treatment related.
Twenty-eight per cent of patients in each treatment arm reported at least one SAE. Over half of the reported SAEs were hematological (primarily neutropenia) or infections/infestations (primarily pneumonia).
Hematological SAEs occurred at comparable frequencies in both treatment arms. Infections/infestations occurred more frequently in patients in the R-CHEMO arm than in patients in the CHEMO arm (9% versus 6% of patients who reported at least one serious infection/infestation). Other SAEs affecting a total of at least 10 patients were gastrointestinal disorders (5% on CHEMO versus 4% on R-CHEMO with at least 1 event), pyrexia (2% in both treatment arms with at least one event), vascular disorders (2% on CHEMO versus 1% on R-CHEMO with at least one event) and cardiac disorders (<1% on CHEMO versus 2% on R-CHEMO with at least one event).
The number of deaths from causes other than lymphoma was similar in both treatment groups (7/403 in the CHEMO arm and 7/404 in the R-CHEMO arm).

Conclusions
MabThera significantly improved the efficacy of chemotherapy in low risk patients less than 60 years of age with diffuse large B-cell lymphoma. Statistically significant improvements were seen for all efficacy parameters studied (TTF, OS and tumor response). The incidence of AEs, SAEs and deaths unrelated to lymphoma were similar to those seen with chemotherapy alone. No new, unexpected safety signals were detected. The therapeutic advantages of MabThera in combination with chemotherapy clearly outweigh the MabThera-related toxicities.

Publications (references, if available)
Pfreundschuh M, Trümper L, Österborg A et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7(5):379-391

Date of report
4/1/2005

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