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

• ClinicalTrials.gov Identifier: NCT00499018
• Recruitment Status: Unknown
• First Posted: July 11, 2007
• Last Update Posted: February 15, 2011
• Sponsor: Fondazione Italiana Linfomi - ETS
• Collaborator: Centro di Riferimento per l'Epidemiologia e la Prev. Oncologica Piemonte
• Information provided by: Fondazione Italiana Linfomi - ETS

Tracking Information

• First Submitted Date: July 10, 2007
• First Posted Date: July 11, 2007
• Last Update Posted Date: February 15, 2011
• Study Start Date: January 2006
• Estimated Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: November 8, 2007): 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). [ Time Frame: 2 years ]
• Original Primary Outcome Measures (submitted: July 10, 2007): 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).

Current Secondary Outcome Measures (submitted: November 8, 2007)

• 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). [ Time Frame: 3 years ]
• To evaluate the efficacy of two different dose-dense + Rituximab chemotherapy regimens in term of 2-years Failure Free Survival (FFS). [ Time Frame: 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). [ Time Frame: 2 years ]
• To evaluate the efficacy of the four different induction arms in terms of 2-years FFS (exploratory analysis). [ Time Frame: 2 years ]

Original Secondary Outcome Measures (submitted: July 10, 2007)

• 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).
• To evaluate the efficacy of two different dose-dense + Rituximab chemotherapy regimens in term of 2-years Failure Free Survival (FFS).
• 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).
• To evaluate the efficacy of the four different induction arms in terms of 2-years FFS (exploratory analysis).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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.

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Diffuse Large B-Cell Lymphoma
• IPI≥2

Intervention

• 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

Study Arms

• Experimental: 1
  R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
  Interventions:

  • 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
• Experimental: 1 BIS
  R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
  Interventions:

  • Drug: Rituximab
  • Drug: Vincristina
  • Drug: Prednisone
  • Drug: Pegfilgrastim
  • Drug: Lenograstim
  • Drug: BCNU
  • Drug: ARA-C
  • Drug: VP-16
  • Procedure: ASCT
  • Drug: Ciclofosfamide
  • Drug: Doxorubicina
  • Drug: Vincristina
• Experimental: 2
  R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2
  Interventions:

  • Drug: Rituximab
  • Drug: Ciclofosfamide
  • Drug: Doxorubicina
  • Drug: Vincristina
  • Drug: Prednisone
  • Drug: Pegfilgrastim
  • Drug: Mitoxantrone
  • Drug: ARA-C
• Experimental: 2 BIS
  R-CHOP14 x 4 Restaging + R-CHOP14 x 4
  Interventions:

  • Drug: Rituximab
  • Drug: Vincristina
  • Drug: Prednisone
  • Drug: Ciclofosfamide
  • Drug: Doxorubicina
  • Drug: Vincristina

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.

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: February 14, 2011): 399
• Original Estimated Enrollment (submitted: July 10, 2007): 376
• Estimated Study Completion Date: September 2013
• Estimated Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT00499018
• Other Study ID Numbers: IIL-DLCL04; EudraCT number 2007-000275-42
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Umberto Vitolo, A.O. San Giovanni Battista - Molinette Torino
• Original Responsible Party: Not Provided
• Current Study Sponsor: Fondazione Italiana Linfomi - ETS
• Original Study Sponsor: Same as current
• 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) -

• PRS Account: Fondazione Italiana Linfomi - ETS
• Verification Date: February 2011