Dose Dense Chemotherapy + Rituximab +/-Intensified High Dose Chemoimmunotherapy With Support of Peripheral Autologous Stem Cell in Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to define an improvement in patients randomized in four different arms: Arm 1: R-MegaCHOP14x4 + R-MAD + MAD + BEAM + ASCT; Arm 1BIS: R-CHOP14x4 + R-MAD + MAD + BEAM + ASCT; Arm 2: R-MegaCHOP14x4 + R-MegaCHOP14x2; Arm 2BIS: R-CHOP14x4 + R-CHOP14x4; Which are different in dose dense chemotherapy + Rituximab with or without intensified high dose chemoimmunotherapy and support of peripheral autologous stem cells.

Official Title
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A Randomised Multicentric Phase III Study for the Treatment of Young Patients With High Risk (IPI 2-3) Diffuse Large B-Cell Lymphoma. Dose Dense Chemotherapy + Rituximab +/- Intensified High Dose Chemoimmunotherapy With Support of Peripheral Autologous Stem Cells.

Conditions
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Diffuse Large B-Cell Lymphoma, IPI≥2

Intervention / Treatment
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* Drug: Rituximab
* Drug: Ciclofosfamide
* Drug: Doxorubicina
* Drug: Vincristina
* Drug: Prednisone
* Drug: Pegfilgrastim
* Drug: Mitoxantrone
* Drug: ARA-C
* Drug: Lenograstim
* Drug: BCNU
* Drug: ARA-C
* Drug: VP-16
* Procedure: ASCT
* Drug: Ciclofosfamide
* Drug: Doxorubicina
* Drug: Vincristina


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-60; Histological confirmed diagnosis of Diffuse Large B-Cell Lymphoma CD20+ (newly diagnosis or shifted from low grade NHL and not previously treated) or of Follicular Lymphoma grade III according to REAL/WHO Classification. Advanced stage II, stage III and stage IV with at least two aa-IPI risk factors. Age-adjusted IPI 2-3. ECOG performance status 0-2. LVEF>45%, measured with echocardiography. Normal hepatic, renal and pulmonary functions. HIV, HCV and HBV negativity. HCV+ admitted only in histologically confirmed absence of replication marks. Positive serology for HBV (occult carriers: AntiHBcAg+, HbsAg-, AntiHBsAg+/-) admitted only upon negativity of weakly positive HBV-DNA test. Life expectancy > 3 months. Negative pregnancy test. Written Informed Consent. Exclusion Criteria: Histological diagnosis of: Lymphoblastic NHL Burkitt's Lymphoma CD 20 negative B-cell Lymphoma grade I-IIIa Follicular Lymphoma Mantle Cell Lymphoma Primary mediastinal NHL with exclusively intrathoracic localization. Age > 60 Stage I disease Age-adjusted IPI 0-1 ECOG-PS>3, if not related to Lymphoma Renal impairment (creatinine>1,2 mg/dl or creatinine clearance < 60ml/min) Hepatic impairment (AST/ALT or bilirubin > 2,5 times normal limit, unless due to Lymphoma) HIV positive patients and/or with HBV or HCV active infection(documented by HBV-DNA and HCV-RNA positive tests) Clinically significant secondary cardiovascular disease e.g. uncontrolled hypertension (resting diastolic blood pressure > 115 mmHG), uncontrolled multifocal cardiac arrhythmias, symptomatic angina pectoris or congestive cardiac failure NYHA class III-IV LFEV<45% Severe diabetes mellitus difficult to control with adequate insulin therapy Severe chronic obstructive pulmonary disease with hypoxemia Active bacterial, viral of fungal infection requiring systemic therapy Concurrent thrombohemolytic disease HIV positivity HBV positivity Positive serology for HBV (occult carriers: AntiHBc+, HbsAg-, AntiHbs+/-) with positive HBV-DNA test HCV positivity in presence of replication marks (HCV+, CRP+, AST 1,5-2 times normal ranges) CNS localization of disease Prior (during last 3 years) or concurrent malignancy except adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix or early stage prostate cancer not requiring systemic therapy, or early breast cancer treated with surgery alone. Any other co.existing medical condition that would preclude study therapy administration Pregnancy or breast-feeding women Inability of the patient to give her/his informed consent Known hypersensitivity or anaphylactic reaction to murine antibodies or proteins

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum 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 |
| --- | --- |
| Experimental: 1<br>R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT | Drug: Rituximab<br>* 375 mg/m2 day 1<br>Drug: Ciclofosfamide<br>* 1200 mg/m2 day 1<br>Drug: Doxorubicina<br>* 70 mg/m2 day 1<br>Drug: Vincristina<br>* 1,4 mg/m2 (max 2 mg) day 1<br>Drug: Prednisone<br>* 100 mg day g 1-5<br>Drug: Pegfilgrastim<br>* 6 mg day +1<br>Drug: Mitoxantrone<br>* 8 mg/m2/days 1-3<br>Drug: ARA-C<br>* 2000 mg/m2/12h day 1 - 3<br>Drug: Lenograstim<br>* 5 μg/Kg/days +2<br>Drug: BCNU<br>* 300 mg/m2 day -7<br>Drug: ARA-C<br>* 200 mg/m2/12 days -6,-5,-4,-3<br>Drug: VP-16<br>* 100 mg/m2/12h days -6,-5,-4,-3<br>Procedure: ASCT<br>* PBSC Reinfusion<br>|
| Experimental: 1 BIS<br>R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT | Drug: Rituximab<br>* 375 mg/m2 day 1<br>Drug: Vincristina<br>* 1,4 mg/m2 (max 2 mg) day 1<br>Drug: Prednisone<br>* 100 mg day g 1-5<br>Drug: Pegfilgrastim<br>* 6 mg day +1<br>Drug: Lenograstim<br>* 5 μg/Kg/days +2<br>Drug: BCNU<br>* 300 mg/m2 day -7<br>Drug: ARA-C<br>* 200 mg/m2/12 days -6,-5,-4,-3<br>Drug: VP-16<br>* 100 mg/m2/12h days -6,-5,-4,-3<br>Procedure: ASCT<br>* PBSC Reinfusion<br>Drug: Ciclofosfamide<br>* 750 mg/m2 day 1<br>Drug: Doxorubicina<br>* 50 mg/m2 day 1<br>Drug: Vincristina<br>* 1,4 mg/m2 (max 2 mg) day 1<br>|
| Experimental: 2<br>R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2 | Drug: Rituximab<br>* 375 mg/m2 day 1<br>Drug: Ciclofosfamide<br>* 1200 mg/m2 day 1<br>Drug: Doxorubicina<br>* 70 mg/m2 day 1<br>Drug: Vincristina<br>* 1,4 mg/m2 (max 2 mg) day 1<br>Drug: Prednisone<br>* 100 mg day g 1-5<br>Drug: Pegfilgrastim<br>* 6 mg day +1<br>Drug: Mitoxantrone<br>* 8 mg/m2/days 1-3<br>Drug: ARA-C<br>* 2000 mg/m2/12h day 1 - 3<br>|
| Experimental: 2 BIS<br>R-CHOP14 x 4 Restaging + R-CHOP14 x 4 | Drug: Rituximab<br>* 375 mg/m2 day 1<br>Drug: Vincristina<br>* 1,4 mg/m2 (max 2 mg) day 1<br>Drug: Prednisone<br>* 100 mg day g 1-5<br>Drug: Ciclofosfamide<br>* 750 mg/m2 day 1<br>Drug: Doxorubicina<br>* 50 mg/m2 day 1<br>Drug: Vincristina<br>* 1,4 mg/m2 (max 2 mg) day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the activity of arms R-MegaCHOP14/R-CHOP14 + R-MAD+BEAM and ASCT and R-MegaCHOP14/R-CHOP14 in terms of 2-years Failure Free Survival (FFS). |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the activity of arms R-MegaCHOP14/R-CHOP14 + R-MAD+BEAM and ASCT and R-MegaCHOP14/R-CHOP14 in terms of 3-years Overall Survival (OS). |  | 3 years | 
| To evaluate the efficacy of two different dose-dense + Rituximab chemotherapy regimens in term of 2-years Failure Free Survival (FFS). |  | 2 years | 
| To evaluate the activity of the first four courses of two different dose dense + Rituximab chemotherapy regimens (standard dose R-CHOP14 or intensified dose R-MegaCHOP14) in terms of Overall Response Rate (ORR) and Complete Remission (RC). |  | 2 years | 
| To evaluate the efficacy of the four different induction arms in terms of 2-years FFS (exploratory analysis). |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Large B-Cell Lymphoma, Rituximab, Autologous Stem Cell Transplantation