Viewing Study NCT00169208



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Last Modification Date: 2024-10-26 @ 9:16 AM
Study NCT ID: NCT00169208
Status: COMPLETED
Last Update Posted: 2019-08-28
First Post: 2005-09-09

Brief Title: Fludarabine Mitoxantrone and Rituximab in Relapsed or Primary Failing Advanced Follicular Non-Hodgkins Lymphoma
Sponsor: Lymphoma Study Association
Organization: Lymphoma Study Association

Study Overview

Official Title: An Open Label Multicenter Non Randomized Phase II Study to Evaluate Anti-tumor Activity and Safety of a Combination of Fludarabine Mitoxantrone and Rituximab in Relapsed or Primary Failing Advanced Follicular Non-Hodgkins Lymphoma
Status: COMPLETED
Status Verified Date: 2019-08
Last Known Status: None
Delayed Posting: No
If Stopped, Why?: Not Stopped
Has Expanded Access: False
If Expanded Access, NCT#: N/A
Has Expanded Access, NCT# Status: N/A
Acronym: None
Brief Summary: This study is a multicentric trial evaluating the efficacy of the RFM regimen in patients aged 18 to 75 years with relapsedrefractory follicular non-Hodgkins lymphoma NHL
Detailed Description: Follicular non Hodgkins lymphomas FL as defined by the Revised European American Lymphoma Classification REAL Classification are usually characterized by a slowly progressive clinical course a transient control by standard chemotherapeutic regimen and a pattern of repeated relapses until ultimately progressive and fatal disease

Standard first line treatment for advanced FL consists of alkylating-based CVP or anthracycline containing regimen in association to interferon alpha CHVPIFN chemotherapy Others approaches have been developed mostly as secondary therapy including purine analogs alone or in combination with alkylators or mitoxantrone high dose therapy with autologous peripheral stem cell transplantation and more recently treatment with the unconjugated chimeric anti-CD20 antibody rituximab to target the CD20 antigen highly expressed on follicular lymphoma cells None of these strategies does appear to give a definitive survival advantage Thus in patients with FL the design of novel combination programs is a major challenge

Combination of fludarabine and mitoxantrone in low grade predominantly Follicular NHL results of phase II studies in relapsed or refractory patients Fludarabine is expected to potentiate other agents through inhibition of DNA polymerase alpha and DNA ligase and its consequent interference with the DNA repair process The addition of mitoxantrone increases the cytotoxic effect of fludarabine in vitro McLaughlin et al developed a combination of fludarabine mitoxantrone and dexamethasone FND which was very effective in 51 patients with recurrent low-grade lymphoma including 65 FL with an overall response rate of 94 47 complete response CR rate The median duration of response in this phase II study was 21 months for CR patients but only 9 months for partial responders PR patients The median survival and failure-free survival times from the time of entry onto the FND study were 34 and 14 months respectively Most major responses were evident after two to four courses of chemotherapy The need for continuation of therapy beyond attainment of remission is suggested by early relapses among patients who had early discontinuation of therapy The predominant toxic effects were myelosuppression and infections neutropenia 500µl in 20 of courses thrombopenia 50000µl in 8 of courses and infections in 12 of courses Non-hematological toxicity was modest

FND appears to be comparable to and less toxic than the combination of etoposide methylprednisolone cytarabine and cisplatin ESHAP one of the most effective regimens available for patients with relapsed indolent lymphoma Others studies have confirmed the significant efficacy and moderate toxicity profile of this combination as salvage therapy in low grade predominantly follicular lymphoma

Moreover the omission of corticosteroids reduces the risk of opportunistic infections while the activity of the combination against indolent lymphoma is maintained

Preliminary data from rituximab studies alone or in combination with chemotherapy in relapsed or refractory low grade NHL In vitro rituximab mediates complement dependent cytotoxicity CDC antibody dependent cellular cytotoxicity ADCC and apoptosis However the mechanism of in vivo anti-lymphoma effect remains largely unknown Rituximab received approval for recurrent follicular lymphoma based on response rates of about 50 including 6 complete responses and duration of responses which compare favorably to that of all other single agents including fludarabine and 2-CdA 15-19 Median time to progression for responders is around 13 months Toxicity of rituximab is low and easily manageable An 8 doses schedule did not show to confer a significant advantage in term of response rate and duration of response over the four doses schedule

Rituximab has been shown to sensitize drug-resistant lymphoma cell lines to killing by cytotoxic drugs including fludarabine

Thus we may hypothesize that the combination of rituximab fludarabine and mitoxantrone might lead to synergistic additive induction of apoptosis through different pathways in lymphoma B-cells which maintain an indolent growth pattern

This approach may provide a means to achieve longer progression free survival in relapsed or refractory patients with FL

We opted for a four induction cycles of rituximab fludarabine and mitoxantrone since

1 Four cycles of a combination of fludarabine and mitoxantrone are generally sufficient to assess response
2 the 4 doses schedule of rituximab which has been the most studied is efficient 3 The omission of dexamethasone does not appear to impair ORR and Duration Response DR of a combination of fludarabine and novantrone Recycling will start on day 28

Subsequently responding patients according the International criteria Working group will have 2 more cycle of a combination of fludarabine and mitoxantrone but no rituximab

Study Oversight

Has Oversight DMC: None
Is a FDA Regulated Drug?: None
Is a FDA Regulated Device?: None
Is an Unapproved Device?: None
Is a PPSD?: None
Is a US Export?: None
Is an FDA AA801 Violation?: None