A Trial Looking at Rituximab and Chemotherapy as a Treatment for Follicular Lymphoma in Elderly Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine whether R-FC is more beneficial that R-CVP in the treatment of older patients (aged 60 or over) with Follicular Lymphoma (FL).

Detailed Description
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FL predominantly affects the elderly, yet the optimum treatment for older patients with the disease has not been defined. The present study aims to address this question by comparing the drug combination that is currently considered the gold-standard (R-CVP) with a newer combination (R-FC) that might be more effective without being significantly more toxic. In order to take into account the balance between efficacy and toxicity, a dual primary endpoint has been employed: progression-free survival and toxicity in the form of grade 3-4 infection.

Official Title
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Purine-Alkylator Combination In Follicular Lymphoma Immuno-Chemotherapy for Older Patients: a Phase III Comparison of First-line R-CVP Versus R-FC

Conditions
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Follicular Lymphoma

Intervention / Treatment
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* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Vincristine
* Drug: Prednisolone
* Drug: Fludarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed follicular lymphoma (grade 1,2, and 3a with material available for central review) Ann Arbor stage II-IV Aged 60 years or over, or aged less than 60 but anthracycline-based therapy contra-indicated No prior systemic therapy (one episode of prior local radiotherapy is allowed) At least one of the following criteria for initiation of treatment: Rapid generalized disease progression in the preceding 3 months Life threatening organ involvement Renal or macroscopic liver infiltration Bone lesions Presence of systemic symptoms or pruritus Haemoglobin < 10 g/dL or WBC < 3.0 × 109/L or platelet counts < 100 × 109/L due to marrow involvement Adequate haematological function (unless abnormalities are related to lymphoma infiltration of the bone marrow): Haemoglobin ≥ 8.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L Written Informed Consent Exclusion Criteria: Overt transformation to diffuse large B-cell lymphoma Grade 3b follicular lymphoma Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningitis) WHO performance status 3 or 4 Impaired renal function defined as estimated Glomerular filtration rate (eGFR) < 30 mL/min using the Modification of Diet in Renal Disease (MDRD) formula Impaired hepatic function defined as serum bilirubin more than twice upper limit of normal (unless due to lymphoma or Gilbert's syndrome) Life expectancy less than 12 months Pre-existing neuropathy Active auto-immune haemolytic anaemia Serological evidence of infection with HIV, hepatitis B (positivity for surface antigen or core antibody) or hepatitis C Allergy to murine proteins Corticosteroid treatment during the last 4 weeks, unless administered at a dose equivalent to no more than prednisolone 20mg/day continuously or a single course of prednisolone 1 mg/kg for up to 7 days Concomitant malignancies except adequately treated localised non-melanoma skin cancer or adequately treated in situ cervical cancer, or cancers that have been in remission for at least 5 years following surgery with curative intent. Major surgery (excluding lymph node biopsy) within 28 days prior to randomisation Serious underlying medical conditions, which could impair the ability of the patient to participate in the trial (e.g. ongoing infection, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease) Treatment within a clinical trial within 30 days prior to trial entry Any other co-existing medical or psychological condition that will preclude participation in the study or compromise ability to give informed consent Adult patient under tutelage (not competent to sign informed consent) Pregnant or lactating women All men or women of reproductive potential, unless using at least two contraceptive precautions, one of which must be a condom

Ages Eligible for Study
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Minimum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: R-CVP<br>Repeated every 21 days for up to 8 cycles with response assessment after 4 cycles. Responders (PR/CR) after 8 cycles will receive Rituximab maintenance therapy for 2 years (12 bi-monthly cycles). | Drug: Rituximab<br>* Rituximab 375mg/m2 IV day 1,repeated every 21 days for 8 cycles. All patients who have achieved a CR or PR to induction therapy will receive rituximab maintenance (375mg/m2 every 2 months for 2 years).<br>* Other names: Mabthera;Drug: Cyclophosphamide<br>* Cyclophosphamide 250mg/m2 PO day 1-3, repeated every 21 days for 4 (R-FC) or 8 cycles (R-CVP)<br>* Other names: Cyclophosphamide monohydrate;Drug: Vincristine<br>* Vincristine 1.4mg/m2 IV day 1,repeated every 21 days for 8 cycles.<br>* Other names: vincristine sulfate;Drug: Prednisolone<br>* Prednisolone 40mg/m2 PO day 1-5, repeated every 21 days for 8 cycles.<br>* Other names: Deltacortril;|
| Experimental: R-FC<br>Repeated every 21 days for 4 cycles. Responders (PR/CR) after 4 cycles will receive 4 further cycles of Rituximab only. Responders after 8 cycles will receive Rituximab maintenance therapy for 2 years (12 bi-monthly cycles). | Drug: Cyclophosphamide<br>* Cyclophosphamide 250mg/m2 PO day 1-3, repeated every 21 days for 4 (R-FC) or 8 cycles (R-CVP)<br>* Other names: Cyclophosphamide monohydrate;Drug: Fludarabine<br>* Fludarabine 40mg/m2 PO day 1-3,repeated every 21 days for 4 cycles<br>* Other names: Fludara;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity | The second primary outcome measure is grade 3-4 infection occurring anytime from the start of treatment until 6 months following the last dose of treatment, and this will be used as the toxicity end-point. Toxicity will be measured according to standard National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 following each cycle of treatment and at each subsequent follow-up visit until 6 months following the last dose of treatment. | 36 months | 
| Progression-free survival |  | 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rates (overall, complete and partial) following initial therapy |  | 24 weeks | 
| Response rates following maintenance therapy |  | 30 months | 
| Response duration |  | 30 months | 
| Overall survival |  | End of study | 
| Time to next treatment |  | End of study | 
| Rate of large cell transformation |  | End of study | 
| Response to second-line therapy |  | 30 months | 
| Number of treatment cycles delivered |  | 30 months | 
| Cumulative dose of individual drugs administered |  | 30 months | 
| Quality of life |  | End of study | 
| Cost effectiveness |  | End of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PACIFICO, Follicular Lymphoma, Non-Hodgkin's Lymphoma, Rituximab, R-CVP, R-FC, Older