Clinical trial NCT00499018: Dose Dense Chemotherapy + Rituximab +/-Intensified High Dose Chemoimmunotherapy With Support of Peripheral Autologous Stem Cell in Diffuse Large B-Cell Lymphoma
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 type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Diffuse Large B-Cell Lymphoma
IPI≥2
Keywords: Large B-Cell Lymphoma
Rituximab
Autologous Stem Cell Transplantation
Lead sponsor: Fondazione Italiana Linfomi - ETS
Sponsor class: OTHER
Collaborators: name: Centro di Riferimento per l'Epidemiologia e la Prev. Oncologica Piemonte
First posted: 2007-07-11
Enrollment: 399
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

1. Age 18-60;
2. 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.
3. Advanced stage II, stage III and stage IV with at least two aa-IPI risk factors.
4. Age-adjusted IPI 2-3.
5. ECOG performance status 0-2.
6. LVEF\>45%, measured with echocardiography.
7. Normal hepatic, renal and pulmonary functions.
8. HIV, HCV and HBV negativity.
9. HCV+ admitted only in histologically confirmed absence of replication marks.
10. Positive serology for HBV (occult carriers: AntiHBcAg+, HbsAg-, AntiHBsAg+/-) admitted only upon negativity of weakly positive HBV-DNA test.
11. Life expectancy \> 3 months.
12. Negative pregnancy test.
13. Written Informed Consent.

Exclusion Criteria:

1. 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.
2. Age \> 60
3. Stage I disease
4. Age-adjusted IPI 0-1
5. ECOG-PS\>3, if not related to Lymphoma
6. Renal impairment (creatinine\>1,2 mg/dl or creatinine clearance \< 60ml/min)
7. Hepatic impairment (AST/ALT or bilirubin \> 2,5 times normal limit, unless due to Lymphoma)
8. HIV positive patients and/or with HBV or HCV active infection(documented by HBV-DNA and HCV-RNA positive tests)
9. 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
10. LFEV\<45%
11. Severe diabetes mellitus difficult to control with adequate insulin therapy
12. Severe chronic obstructive pulmonary disease with hypoxemia
13. Active bacterial, viral of fungal infection requiring systemic therapy
14. Concurrent thrombohemolytic disease
15. HIV positivity
16. HBV positivity
17. Positive serology for HBV (occult carriers: AntiHBc+, HbsAg-, AntiHbs+/-) with positive HBV-DNA test
18. HCV positivity in presence of replication marks (HCV+, CRP+, AST 1,5-2 times normal ranges)
19. CNS localization of disease
20. 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
21. Pregnancy or breast-feeding women
22. Inability of the patient to give her/his informed consent
23. Known hypersensitivity or anaphylactic reaction to murine antibodies or proteins

Primary outcomes:
measure: 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).
timeFrame: 2 years
Secondary outcomes:
measure: 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).
timeFrame: 3 years
measure: To evaluate the efficacy of two different dose-dense + Rituximab chemotherapy regimens in term of 2-years Failure Free Survival (FFS).
timeFrame: 2 years
measure: 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).
timeFrame: 2 years
measure: To evaluate the efficacy of the four different induction arms in terms of 2-years FFS (exploratory analysis).
timeFrame: 2 years
Other outcomes:
Locations:
city: Nocera Inferiore
country: Italy
facility: Ospedale Umberto I - DH Oncoematologico
state: Salerno
city: Mestre
country: Italy
facility: Ospedale Civile Umberto I
state: Venezia
city: Mirano
country: Italy
facility: Osp. Calvi, Noale
state: Venezia
city: Alessandria
country: Italy
facility: Az. Osp. SS. Antonio e Biagio e Cesare Arrigo
city: Asti
country: Italy
facility: Ospedale Cardinal Massaia
city: Aviano - PN
country: Italy
facility: Centro di Riferimento Oncologico
city: Bari
country: Italy
facility: Azienda Ospedale Policlinico Consorziale
city: Bari
country: Italy
facility: IRCC Istituto tumori Ematologia
city: Biella
country: Italy
facility: Osp. Degli Infermi
city: Bologna
country: Italy
facility: Ospedale Policlinico S. Orsola Malpighi
city: Brescia
country: Italy
facility: Spedali Civili
city: Brescia
country: Italy
facility: UTMO Ematologia Università Spedali Civili
city: Brindisi
country: Italy
facility: Stabilimento "Perrino"
city: Busto Arsizio - VA
country: Italy
facility: Ospedale di Circolo
city: Cagliari
country: Italy
facility: Ospedale Armando Businco
city: Campobasso
country: Italy
facility: Università Cattolica del Sacro Cuore
city: Candiolo (TO)
country: Italy
facility: IRCC
city: Catanzaro
country: Italy
facility: Ospedale Pugliese
city: Cesena - FC
country: Italy
facility: Ospedale Bufalini
city: Ciriè - TO
country: Italy
facility: Stabilimento Ospedaliero
city: Civitanova Marche (MC)
country: Italy
facility: Ospedale Generale di Zona
city: Cosenza
country: Italy
facility: Presidio Ospedaliero Annunziata
city: Cremona
country: Italy
facility: Istituti Ospitalieri
city: Firenze
country: Italy
facility: Az. Ospedaliero Universitaria Careggi
city: Forlì
country: Italy
facility: Stabilimento Forlì
city: Genova
country: Italy
facility: Azienda Universitaria San Martino
city: Ivrea
country: Italy
facility: A.S.L. 9
city: La Spezia
country: Italy
facility: Ospedale Felettino
city: Lecce
country: Italy
facility: Istituto Vito Fazzi
city: Messina
country: Italy
facility: Azienda Ospedaliera Papardo
city: Messina
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico Gaetano Martino
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia
city: Milano
country: Italy
facility: Osp. San Carlo Borromeo
city: Milano
country: Italy
facility: Ospedale Cà Grande - Niguarda
city: Milano
country: Italy
facility: Ospedale Fatebenefratelli
city: Milano
country: Italy
facility: Presidio Osp. Maggiore Policlinico
city: Modena
country: Italy
facility: Azienda Ospedaliera Policlinico
city: Monza
country: Italy
facility: Ospedale S. Gerardo
city: Napoli
country: Italy
facility: Università degli Studi Federico II
city: Novara
country: Italy
facility: Osp. Maggiore Della Carità
city: Nuoro
country: Italy
facility: Ospedale S. Francesco
city: Orbassano (TO)
country: Italy
facility: Ospedale San Luigi
city: Padova
country: Italy
facility: Azienda Ospedaliera
city: Parma
country: Italy
facility: Università degli Studi
city: Pavia
country: Italy
facility: Fond. Maugeri - Centro medico
city: Pavia
country: Italy
facility: Ospedale Policlinico San Matteo
city: Piacenza
country: Italy
facility: Ospedale di Piacenza
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana
city: Potenza
country: Italy
facility: Azienda Ospedaliera Ospedale San Carlo
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci
city: Reggio Calabria
country: Italy
facility: Ospedale Bianchi Melacrino Morelli
city: Reggio Emilia
country: Italy
facility: Ospedale Santa Maria Nuova
city: Rionero in Vulture (PZ)
country: Italy
facility: Ospedale Oncologico Regionale
city: Roma
country: Italy
facility: Istituto Regina Elena
city: Roma
country: Italy
facility: Ospedale S. Eugenio
city: Roma
country: Italy
facility: Policlinico Universitario A. Gemelli
city: Roma
country: Italy
facility: Policlinico Universitario Campus Biomedico
city: Roma
country: Italy
facility: Università degli Studi di Roma "La Sapienza"
city: Roma
country: Italy
facility: Università degli Studi di Roma 'Tor Vergata'
city: Ronciglione (VT)
country: Italy
facility: Ospedale di Ronciglione
city: Rozzano - MI
country: Italy
facility: Istituto Clinico Humanitas
city: San Giovanni Rotondo (FG)
country: Italy
facility: Casa Sollievo della Sofferenza
city: Sassari
country: Italy
facility: Ospedale SS.Annunziata
city: Siena
country: Italy
facility: Spedali Riuniti
city: Sondalo
country: Italy
facility: Ospedale Morelli
city: Taranto
country: Italy
facility: Stabilimento SS. Annunziata
city: Terni
country: Italy
facility: Azienda Ospedaliera di Perugia
city: Torino
country: Italy
facility: Osp. S. Giovanni Battista "Molinette"
city: Treviso
country: Italy
facility: Ospedale Ca Focello
city: Treviso
country: Italy
facility: Presidio Ospedaliero di Vittorio Veneto
city: Tricase (LE)
country: Italy
facility: Ospedale Generale Prov. Cardinale G. Panico
city: Udine
country: Italy
facility: Policlinico Universitario
city: Varese
country: Italy
facility: Osp. di Circolo e Fondazione Macchi
city: Verbania
country: Italy
facility: Stabilimento Ospedaliero
city: Vercelli
country: Italy
facility: Osp. Sant'Andrea Divisioen di Onco-Ematologia
Study officials:
affiliation: S.C. Ematologia II - OSP.S. GIOV.BATTISTA MOLINETTE - TORINO (TO) -
name: Umberto Vitolo, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Derenzini E, Mazzara S, Melle F, Motta G, Fabbri M, Bruna R, Agostinelli C, Cesano A, Corsini CA, Chen N, Righi S, Sabattini E, Chiappella A, Calleri A, Fiori S, Tabanelli V, Cabras A, Pruneri G, Vitolo U, Gianni AM, Rambaldi A, Corradini P, Zinzani PL, Tarella C, Pileri S. A three-gene signature based on MYC, BCL-2 and NFKBIA improves risk stratification in diffuse large B-cell lymphoma. Haematologica. 2021 Sep 1;106(9):2405-2416. doi: 10.3324/haematol.2019.236455.
citation: Chiappella A, Martelli M, Angelucci E, Brusamolino E, Evangelista A, Carella AM, Stelitano C, Rossi G, Balzarotti M, Merli F, Gaidano G, Pavone V, Rigacci L, Zaja F, D'Arco A, Cascavilla N, Russo E, Castellino A, Gotti M, Congiu AG, Cabras MG, Tucci A, Agostinelli C, Ciccone G, Pileri SA, Vitolo U. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017 Aug;18(8):1076-1088. doi: 10.1016/S1470-2045(17)30444-8. Epub 2017 Jun 28.