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Clinical Trial Result Information
Protocol number
M39048
Title of Study
In vivo purging with High Dose Sequential chemotherapy and Rituximab monoclonal antibody (R-HDS), in newly diagnosed mantle cell lymphoma.
Sponsor
Roche S.p.a.
Company division
Pharmaceutical
Product name
MabThera/Rituxan
Generic name
rituximab
Therapeutic area
Mantle Cell Lymphoma
Clinical study summary
This was an open, non-comparative, multicenter study in patients with newly diagnosed mantle cell lymphoma, to investigate the efficacy and safety of MabThera (rituximab) + high dose sequential chemotherapy.
Study center(s)
6 centers in Italy.
Phase of development
II
Objectives
Primary: To evaluate the activity of MabThera + high-dose sequential chemotherapy (R-HDS) combination, in terms of durable complete clinical remission, in newly diagnosed mantle cell non-Hodgkin's lymphoma; to evaluate the safety of R-HDS combination.
Secondary: To evaluate the molecular activity of R-HDS combination, in terms of molecular remission in the bone marrow and peripheral blood at the end of the treatment and at the end of the study in patients with clinical complete remission; to evaluate the overall clinical response at the end of treatment and at the end of study; to evaluate overall survival; to evaluate the ability of purging in vivo of MabThera administered in combination with high dose cyclophosphamide and high dose cytarabine.
Methodology
Eligible patients were exposed to a 35 week period of high dose chemotherapy (see below), during which they received 6 iv infusions of MabThera, at intervals. The effect of the treatment on clinical response was measured at the end of treatment, and at the end of the study.
Number of patients (planned/analyzed)
Planned: 93 - Entered: 37.
Diagnosis and main criteria for inclusion
Adult male or female patients with newly diagnosed mantle cell lymphoma. Histologically-confirmed mantle cell NHL. Age >18 years and <60 years with ECOG performance status 0-3, or age from 60 to 65 years with an ECOG performance status 0-2. CD20 positive B cell lymphoma. Bidimensionally measurable disease in at least one site which has not been irradiated.
Test product, dose and mode of administration or test procedure
Six infusions of 375mg/m2 MabThera (rituximab) as infusion on day 3 and day 11 of phase I and II and day 0 and day 8 of phase V - The chemotherapy protocol extended across 35 weeks:
1 APO cycle (2 weeks) + approx 2 weeks interval + 2 DHAP cycles (4 weeks) + approx 3 weeks interval + phase I HD-cyclophosphamide 2 weeks + approx 3 weeks interval + phase II cytarabine 3 weeks + approx 3 weeks interval + phase III HD melphalan 2 weeks + approx 3 weeks interval + phase IV HD mitoantrone + melphalan approx 2 weeks + approx 3 weeks interval + phase V MabThera 1 week.
Duration of treatment
35 weeks
Reference therapy, dose and mode of administration or reference procedure
N/A.
Criteria for evaluation (efficacy, safety)
Efficacy: Primary: Rate of durable complete clinical response (CR) defined as CR that lasted for at least 24 months.
Secondary: Molecular response rate in the bone marrow and peripheral blood at the end of treatment and at the end of the study in patients with clinical complete remission; rates of complete response (CR), complete response unconfirmed (CRu), partial response (PR), stable disease (SD) and progressive disease (PD) at the end of treatment and at the end of the study; rate of relapse at the end of the study; response duration; disease-free survival; progression-free survival; event-free survival; overall survival.
Safety: Adverse event rates; changes in laboratory tests vs. baseline.
Statistical methods
Response rates were analyzed descriptively.
Overall survival was calculated from the first dose of the first study drug to the death or last observation (censored). Progression free survival was calculated from the first dose of the first study drug to the disease progression or death from NHL or last observation (censored). Event free survival was calculated from the first dose of the first study drug to the time of failure or last observation (censored). Failure was defined as the first among relapse/progression, withdrawal from the study due to adverse event, change of treatment or death from any cause.
Curves of overall survival, progression free survival and event free survival were estimated using the Kaplan and Meier method.
Safety data were analyzed descriptively.
Summary (efficacy, safety, other results)
Efficacy: Primary: At the end of treatment, including radiotherapy, a documented complete clinical response was achieved in 17 patients (47.2%) and an unconfirmed complete clinical response was achieved in 8 patients (22.2%), leading to a total complete response rate of 69.4%. The mean duration of the complete responses (both confirmed and unconfirmed) was 20.8 +/- 7.3 months, median 23.9 months (range 5.8-30.1 months). A complete response for ≥24 months was achieved by 13 patients, leading to a durable both confirmed and unconfirmed response rate of 36.1%.
Molecular response: Molecular status was missing in 4 patients at baseline. Molecular remission was achieved at the end of treatment in 16 patients (44.4%), of whom 15 (41.7%) had a confirmed or unconfirmed clinical response. Data was missing at end of treatment in nearly all the remaining patients (n=18), so failure to achieve a molecular remission at end of treatment was documented only in 2 patients (5.6%). At the end of the 24-month follow-up the molecular remission was maintained in 6 patients (16.7%).
Overall clinical response: At the end of treatment the following clinical responses were achieved: 17 confirmed complete clinical responses (47.2%), 8 unconfirmed complete clinical responses (22.2%), 1 partial clinical response (2.8%) and 3 abscence of response with progression of disease (8.3% - 2 patients dropped out before end of treatment due to progression). Information on clinical response was missing in the remaining 7 (19.4%) patients because they dropped out due to drug related adverse events before end of treatment and the evaluation of response was not performed. Of 25 CR/CRu, two cases of relapse were documented after 6 months of follow-up (5.6%). Thirteen (36.1%) patients reported complete clinical or unconfirmed complete clinical response after 24 months of follow-up. For ten (27.8%) patients response was not documented as 4 patients dropped out of the study without reassessment of response and 6 patients were evaluated before 690 days of follow-up.
Event Free, Progression Free and Overall Survival
The median follow-up time calculated from the first dose of study drug was 24.4 months.
Mean +/- SD event-free survival was 21.1 +/- 13.2 months (range: 3.8-43.1 months).
The median of event free survival estimated by Kaplan Meier method was not reached. At the median time of follow-up (24.4 months) the event free survival was 51%, while the 25th percentile was ~ 11 months (95CI 8-13 months).
Mean +/- SD progression-free survival, was 23.4 +/- 12.9 months (range: 3.8-43.1 months); median progression-free survival amounted to 18.8 months.
Mean +/- SD overall survival, was 23.8 +/- 12.9 months (range: 3.8-43.1 months); median survival amounted to 24.4 months.
MabThera activity
The results of bone marrow and/or peripheral blood PCR analysis at baseline and at end of treatment were available in 18 patients: 11 patients with a confirmed complete response, 6 patients with an unconfirmed complete response and one patient with a partial response.
In the 12 patients whose bone marrow had been analyzed, only the results related to bc1-1/JH were available. Out of the eight patients whose bone marrow was bc1/JH positive, seven were negative at end of treatment; three patients with a bc1/JH negative bone marrow at baseline remained negative and the other became postive.
In the 12 patients whose peripheral blood had been analyzed, results related to bc1-1/JH were available in 9; seven were bc1-1/JH positive at baseline and became negative at end of treatment, whereas the eighth was negative and remained negative, the ninth was positive and remained positive. Results related to the CDR III region were available in 4 patients, who were all positive at baseline and became negative at end of treatment; they continued to be negative during follow-up.
Bone marrow and peripheral blood documentation was available in 4 patients, one with a confirmed complete response, two with an unconfirmed complete response and in one patient with a partial response. Both the bone marrow and peripheral blood of these 4 patients were positive at baseline and became negative at end of treatment.
Safety: Nearly all patients experienced a life-threatening or intolerable adverse event (62.2%) or a severe adverse event (32.4%). Three patients died of a serious adverse event (SAE) (8.1%), one (septic shock) considered related to study treatment, and overall 21 (56.8%) experienced a SAE.
The adverse events involved most commonly, were 1) the blood and lymphatic system (83.8% of patients), mainly thrombocytopenia (73.0%) neutropenia (51.4%), anemia and leucopenia (21.6%) 2) the body as a whole (73.0%) mainly fever (70.3%) 3) infections/infestations (51.4%), mainly herpes zoster (18.9%) and Staphylococcal sepsis (13.5%) and 4) respiratory, thoracic and mediastinal disorders (24.3%), mainly pneumonia (13.5%).
Thrombocytopenia, neutropenia and fever were the most common adverse events during all the phases, except phase V, whereas infections and infestations began to appear frequently during phase II and continued to be fairly frequent during phase III and IV.
Few adverse events occurred in phase V, during which only MabThera was given. In this phase the frequency of the most common adverse events, fever, and infections and infestations amounted to only 5%. The most common adverse events during follow-up were blood and lymphatic system disorders (18.9%), mainly thrombocytopenia (8.1%), and infections and infestations (16.2%), mainly Herpes zoster infection (10.8%).
Nearly all the patients reported adverse reactions to treatment (n=35). The most common were very similar to the most common adverse events; 1) disorders of the blood and lymphatic system (75.7% of patients), mainly thrombocytopenia (59.5%) and neutropenia (51.4%); 2) disorders related to the body as a whole (73.0%), mainly fever (67.6%); 3) infections and infestations (45.9%), mainly herpes zoster (16.2%); and 4) respiratory, thoracic and mediastinal disorders, mainly pneumonia (10.8%).
The adverse reactions were moderate to severe in intensity, with the exception of 20 mild adverse reactions (all isolated cases except 5 cases of mild fever) and a number of life-threatening adverse reactions. Most of the life-threatening adverse reactions were disorders affecting the blood and lymphatic system: 14 cases of thrombocytopenia (37.8% of patients), 11 cases of neutropenia (29.7%), 3 cases of leucopenia (8.1%) and isolated cases of anemia and bone marrow failure. Other life-threatening adverse reactions were isolated cases of myocardial ischemia, mucosal inflammation, herpetic keratits, fungal pneumonia, pseudomonas sepsis, sepsis, septic shock, reduction in ejection fraction, paresthesias, acute respiratory failure, hemoptysis and hemorrhage.
Conclusions
This study suggests that sequential treatment with MabThera and high dose chemotherapy preceded by 1 APO cycle and 2 DHAP cycles and associated with leukapheresis + autotransplantation of harvested stem cells, was reasonably well tolerated and was effective as first-line therapy for mantle cell lymphoma in terms of induction of a clinical response lasting at least 24 months. However, no definitive conclusions can be drawn in view of the small sample size in this study.
Date of report
8/7/2007
Click here for the protocol registry listing of this trial.
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