DLCL04: Dose Dense Chemotherapy + Rituximab +/-Intensified High Dose Chemoimmunotherapy With Support of Peripheral Autologous Stem Cell in Diffuse Large B-Cell Lymphoma

Sponsor

Fondazione Italiana Linfomi ONLUS (Other)

Overall Status

Unknown status

CT.gov ID

NCT00499018

Collaborator

Centro di Riferimento per l'Epidemiologia e la Prev. Oncologica Piemonte (Other)

399

Enrollment

Locations

Arms

Duration (Months)

5.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-Cell Lymphoma IPI≥2	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	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

399 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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.

Study Start Date :

Jan 1, 2006

Anticipated Primary Completion Date :

Jun 1, 2011

Anticipated Study Completion Date :

Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT	Drug: Rituximab 375 mg/m2 day 1 Drug: Ciclofosfamide 1200 mg/m2 day 1 Drug: Doxorubicina 70 mg/m2 day 1 Drug: Vincristina 1,4 mg/m2 (max 2 mg) day 1 Drug: Prednisone 100 mg day g 1-5 Drug: Pegfilgrastim 6 mg day +1 Drug: Mitoxantrone 8 mg/m2/days 1-3 Drug: ARA-C 2000 mg/m2/12h day 1 - 3 Drug: Lenograstim 5 μg/Kg/days +2 Drug: BCNU 300 mg/m2 day -7 Drug: ARA-C 200 mg/m2/12 days -6,-5,-4,-3 Drug: VP-16 100 mg/m2/12h days -6,-5,-4,-3 Procedure: ASCT PBSC Reinfusion
Experimental: 1 BIS R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT	Drug: Rituximab 375 mg/m2 day 1 Drug: Vincristina 1,4 mg/m2 (max 2 mg) day 1 Drug: Prednisone 100 mg day g 1-5 Drug: Pegfilgrastim 6 mg day +1 Drug: Lenograstim 5 μg/Kg/days +2 Drug: BCNU 300 mg/m2 day -7 Drug: ARA-C 200 mg/m2/12 days -6,-5,-4,-3 Drug: VP-16 100 mg/m2/12h days -6,-5,-4,-3 Procedure: ASCT PBSC Reinfusion Drug: Ciclofosfamide 750 mg/m2 day 1 Drug: Doxorubicina 50 mg/m2 day 1 Drug: Vincristina 1,4 mg/m2 (max 2 mg) day 1
Experimental: 2 R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2	Drug: Rituximab 375 mg/m2 day 1 Drug: Ciclofosfamide 1200 mg/m2 day 1 Drug: Doxorubicina 70 mg/m2 day 1 Drug: Vincristina 1,4 mg/m2 (max 2 mg) day 1 Drug: Prednisone 100 mg day g 1-5 Drug: Pegfilgrastim 6 mg day +1 Drug: Mitoxantrone 8 mg/m2/days 1-3 Drug: ARA-C 2000 mg/m2/12h day 1 - 3
Experimental: 2 BIS R-CHOP14 x 4 Restaging + R-CHOP14 x 4	Drug: Rituximab 375 mg/m2 day 1 Drug: Vincristina 1,4 mg/m2 (max 2 mg) day 1 Drug: Prednisone 100 mg day g 1-5 Drug: Ciclofosfamide 750 mg/m2 day 1 Drug: Doxorubicina 50 mg/m2 day 1 Drug: Vincristina 1,4 mg/m2 (max 2 mg) day 1

Outcome Measures

Primary Outcome Measures

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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country
1	Ospedale Umberto I - DH Oncoematologico	Nocera Inferiore	Salerno	Italy
2	Ospedale Civile Umberto I	Mestre	Venezia	Italy
3	Osp. Calvi, Noale	Mirano	Venezia	Italy
4	Az. Osp. SS. Antonio e Biagio e Cesare Arrigo	Alessandria		Italy
5	Ospedale Cardinal Massaia	Asti		Italy
6	Centro di Riferimento Oncologico	Aviano - PN		Italy
7	Azienda Ospedale Policlinico Consorziale	Bari		Italy
8	IRCC Istituto tumori Ematologia	Bari		Italy
9	Osp. Degli Infermi	Biella		Italy
10	Ospedale Policlinico S. Orsola Malpighi	Bologna		Italy
11	Spedali Civili	Brescia		Italy
12	UTMO Ematologia Università Spedali Civili	Brescia		Italy
13	Stabilimento "Perrino"	Brindisi		Italy
14	Ospedale di Circolo	Busto Arsizio - VA		Italy
15	Ospedale Armando Businco	Cagliari		Italy
16	Università Cattolica del Sacro Cuore	Campobasso		Italy
17	IRCC	Candiolo (TO)		Italy
18	Ospedale Pugliese	Catanzaro		Italy
19	Ospedale Bufalini	Cesena - FC		Italy
20	Stabilimento Ospedaliero	Ciriè - TO		Italy
21	Ospedale Generale di Zona	Civitanova Marche (MC)		Italy
22	Presidio Ospedaliero Annunziata	Cosenza		Italy
23	Istituti Ospitalieri	Cremona		Italy
24	Az. Ospedaliero Universitaria Careggi	Firenze		Italy
25	Stabilimento Forlì	Forlì		Italy
26	Azienda Universitaria San Martino	Genova		Italy
27	A.S.L. 9	Ivrea		Italy
28	Ospedale Felettino	La Spezia		Italy
29	Istituto Vito Fazzi	Lecce		Italy
30	Azienda Ospedaliera Papardo	Messina		Italy
31	Azienda Ospedaliero Universitaria Policlinico Gaetano Martino	Messina		Italy
32	Istituto Europeo di Oncologia	Milano		Italy
33	Osp. San Carlo Borromeo	Milano		Italy
34	Ospedale Cà Grande - Niguarda	Milano		Italy
35	Ospedale Fatebenefratelli	Milano		Italy
36	Presidio Osp. Maggiore Policlinico	Milano		Italy
37	Azienda Ospedaliera Policlinico	Modena		Italy
38	Ospedale S. Gerardo	Monza		Italy
39	Università degli Studi Federico II	Napoli		Italy
40	Osp. Maggiore Della Carità	Novara		Italy
41	Ospedale S. Francesco	Nuoro		Italy
42	Ospedale San Luigi	Orbassano (TO)		Italy
43	Azienda Ospedaliera	Padova		Italy
44	Università degli Studi	Parma		Italy
45	Fond. Maugeri - Centro medico	Pavia		Italy
46	Ospedale Policlinico San Matteo	Pavia		Italy
47	Ospedale di Piacenza	Piacenza		Italy
48	Azienda Ospedaliero Universitaria Pisana	Pisa		Italy
49	Azienda Ospedaliera Ospedale San Carlo	Potenza		Italy
50	Ospedale Santa Maria delle Croci	Ravenna		Italy
51	Ospedale Bianchi Melacrino Morelli	Reggio Calabria		Italy
52	Ospedale Santa Maria Nuova	Reggio Emilia		Italy
53	Ospedale Oncologico Regionale	Rionero in Vulture (PZ)		Italy
54	Istituto Regina Elena	Roma		Italy
55	Ospedale S. Eugenio	Roma		Italy
56	Policlinico Universitario A. Gemelli	Roma		Italy
57	Policlinico Universitario Campus Biomedico	Roma		Italy
58	Università degli Studi di Roma "La Sapienza"	Roma		Italy
59	Università degli Studi di Roma 'Tor Vergata'	Roma		Italy
60	Ospedale di Ronciglione	Ronciglione (VT)		Italy
61	Istituto Clinico Humanitas	Rozzano - MI		Italy
62	Casa Sollievo della Sofferenza	San Giovanni Rotondo (FG)		Italy
63	Ospedale SS.Annunziata	Sassari		Italy
64	Spedali Riuniti	Siena		Italy
65	Ospedale Morelli	Sondalo		Italy
66	Stabilimento SS. Annunziata	Taranto		Italy
67	Azienda Ospedaliera di Perugia	Terni		Italy
68	Osp. S. Giovanni Battista "Molinette"	Torino		Italy
69	Ospedale Ca Focello	Treviso		Italy
70	Presidio Ospedaliero di Vittorio Veneto	Treviso		Italy
71	Ospedale Generale Prov. Cardinale G. Panico	Tricase (LE)		Italy
72	Policlinico Universitario	Udine		Italy
73	Osp. di Circolo e Fondazione Macchi	Varese		Italy
74	Stabilimento Ospedaliero	Verbania		Italy
75	Osp. Sant'Andrea Divisioen di Onco-Ematologia	Vercelli		Italy