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

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.

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.

Study Overview

• Status: Unknown
• Conditions: Diffuse Large B-Cell Lymphoma; IPI≥2
• Intervention / Treatment: 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

• Study Type: Interventional
• Enrollment (Anticipated): 399
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Alessandria, Italy
    • Az. Osp. SS. Antonio e Biagio e Cesare Arrigo
  • Asti, Italy
    • Ospedale Cardinal Massaia
  • Aviano - PN, Italy
    • Centro di Riferimento Oncologico
  • Bari, Italy
    • IRCC Istituto tumori Ematologia
  • Bari, Italy
    • Azienda Ospedale Policlinico Consorziale
  • Biella, Italy
    • Osp. degli Infermi
  • Bologna, Italy
    • Ospedale Policlinico S. Orsola Malpighi
  • Brescia, Italy
    • Spedali Civili
  • Brescia, Italy
    • UTMO Ematologia Università Spedali Civili
  • Brindisi, Italy
    • Stabilimento "Perrino"
  • Busto Arsizio - VA, Italy
    • Ospedale di Circolo
  • Cagliari, Italy
    • Ospedale Armando Businco
  • Campobasso, Italy
    • Universita Cattolica del Sacro Cuore
  • Candiolo (TO), Italy
    • IRCC
  • Catanzaro, Italy
    • Ospedale Pugliese
  • Cesena - FC, Italy
    • Ospedale Bufalini
  • Ciriè - TO, Italy
    • Stabilimento Ospedaliero
  • Civitanova Marche (MC), Italy
    • Ospedale Generale di Zona
  • Cosenza, Italy
    • Presidio Ospedaliero Annunziata
  • Cremona, Italy
    • Istituti Ospitalieri
  • Firenze, Italy
    • Az. Ospedaliero Universitaria Careggi
  • Forlì, Italy
    • Stabilimento Forlì
  • Genova, Italy
    • Azienda Universitaria San Martino
  • Ivrea, Italy
    • A.S.L. 9
  • La Spezia, Italy
    • Ospedale Felettino
  • Lecce, Italy
    • Istituto Vito Fazzi
  • Messina, Italy
    • Azienda Ospedaliero Universitaria Policlinico Gaetano Martino
  • Messina, Italy
    • Azienda Ospedaliera Papardo
  • Milano, Italy
    • Istituto Europeo di Oncologia
  • Milano, Italy
    • Ospedale Fatebenefratelli
  • Milano, Italy
    • Osp. San Carlo Borromeo
  • Milano, Italy
    • Ospedale Cà Grande - Niguarda
  • Milano, Italy
    • Presidio Osp. Maggiore Policlinico
  • Modena, Italy
    • Azienda Ospedaliera Policlinico
  • Monza, Italy
    • Ospedale S. Gerardo
  • Napoli, Italy
    • Università degli studi Federico II
  • Novara, Italy
    • Osp. Maggiore Della Carità
  • Nuoro, Italy
    • Ospedale S. Francesco
  • Orbassano (TO), Italy
    • Ospedale San Luigi
  • Padova, Italy
    • Azienda Ospedaliera
  • Parma, Italy
    • Università degli Studi
  • Pavia, Italy
    • Fond. Maugeri - Centro medico
  • Pavia, Italy
    • Ospedale Policlinico San Matteo
  • Piacenza, Italy
    • Ospedale di Piacenza
  • Pisa, Italy
    • Azienda Ospedaliero Universitaria Pisana
  • Potenza, Italy
    • Azienda Ospedaliera Ospedale San Carlo
  • Ravenna, Italy
    • Ospedale Santa Maria delle Croci
  • Reggio Calabria, Italy
    • Ospedale Bianchi Melacrino Morelli
  • Reggio Emilia, Italy
    • Ospedale Santa Maria Nuova
  • Rionero in Vulture (PZ), Italy
    • Ospedale Oncologico Regionale
  • Roma, Italy
    • Policlinico Universitario A. Gemelli
  • Roma, Italy
    • Ospedale S. Eugenio
  • Roma, Italy
    • Istituto Regina Elena
  • Roma, Italy
    • Policlinico Universitario Campus Biomedico
  • Roma, Italy
    • Università degli studi di Roma "La Sapienza"
  • Roma, Italy
    • Universita Degli Studi di Roma 'Tor Vergata'
  • Ronciglione (VT), Italy
    • Ospedale di Ronciglione
  • Rozzano - MI, Italy
    • Istituto Clinico Humanitas
  • San Giovanni Rotondo (FG), Italy
    • Casa Sollievo della Sofferenza
  • Sassari, Italy
    • Ospedale SS.Annunziata
  • Siena, Italy
    • Spedali Riuniti
  • Sondalo, Italy
    • Ospedale Morelli
  • Taranto, Italy
    • Stabilimento SS. Annunziata
  • Terni, Italy
    • Azienda Ospedaliera di Perugia
  • Torino, Italy
    • Osp. S. Giovanni Battista "Molinette"
  • Treviso, Italy
    • Ospedale Ca Focello
  • Treviso, Italy
    • Presidio Ospedaliero di Vittorio Veneto
  • Tricase (LE), Italy
    • Ospedale Generale Prov. Cardinale G. Panico
  • Udine, Italy
    • Policlinico Universitario
  • Varese, Italy
    • Osp. di Circolo e Fondazione Macchi
  • Verbania, Italy
    • Stabilimento Ospedaliero
  • Vercelli, Italy
    • Osp. Sant'Andrea Divisioen di Onco-Ematologia
  • Salerno
    • Nocera Inferiore, Salerno, Italy
      • Ospedale Umberto I - DH Oncoematologico
  • Venezia
    • Mestre, Venezia, Italy
      • Ospedale Civile Umberto I
    • Mirano, Venezia, Italy
      • Osp. Calvi, Noale

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / 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; Drug: Ciclofosfamide; 750 mg/m2 day 1; Drug: Doxorubicina; 50 mg/m2 day 1
Experimental: 1 BIS; R-CHOP14 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: 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; Drug: Ciclofosfamide; 750 mg/m2 day 1; Drug: Doxorubicina; 50 mg/m2 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; Drug: ARA-C; 200 mg/m2/12 days -6,-5,-4,-3; Drug: Ciclofosfamide; 750 mg/m2 day 1; Drug: Doxorubicina; 50 mg/m2 day 1
Experimental: 2 BIS; R-CHOP14 x 4 Restaging + R-CHOP14 x 4	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: Ciclofosfamide; 750 mg/m2 day 1; Drug: Doxorubicina; 50 mg/m2 day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Fondazione Italiana Linfomi ONLUS
• Collaborators: Centro di Riferimento per l'Epidemiologia e la Prev. Oncologica Piemonte
• Investigators: Principal Investigator: Umberto Vitolo, MD, S.C. Ematologia II - OSP.S. GIOV.BATTISTA MOLINETTE - TORINO (TO) -

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Anticipated): June 1, 2011
• Study Completion (Anticipated): September 1, 2013

Study Registration Dates

• First Submitted: July 10, 2007
• First Submitted That Met QC Criteria: July 10, 2007
• First Posted (Estimate): July 11, 2007

Study Record Updates

• Last Update Posted (Estimate): February 15, 2011
• Last Update Submitted That Met QC Criteria: February 14, 2011
• Last Verified: February 1, 2011

More Information

Terms related to this study

• Keywords: Rituximab; Autologous Stem Cell Transplantation; Large B-Cell Lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Cyclophosphamide; Rituximab; Lenograstim; Prednisone; Doxorubicin; Liposomal doxorubicin; Cytarabine; Vincristine; Mitoxantrone
• Other Study ID Numbers: IIL-DLCL04; EudraCT number 2007-000275-42