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

Phase 3

• Conditions: Diffuse Large B-Cell Lymphoma; IPI≥2
• Interventions: Drug: Rituximab; Drug: Vincristina; Drug: Ciclofosfamide; Drug: Prednisone; Drug: Doxorubicina; Drug: Pegfilgrastim; Drug: Mitoxantrone; Drug: ARA-C; Drug: Lenograstim; Drug: BCNU; Drug: VP-16; Procedure: ASCT

• Registration Number: NCT00499018
• Lead Sponsor: Fondazione Italiana Linfomi - ETS

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 available

Study Timeline

• Study Start: 2006-01
• Study First Submitted: 2007-07-10
• Study First Submitted QC: 2007-07-10
• Study First Posted: 2007-07-11
• Status Verified: 2011-02
• Last Update Submitted: 2011-02-14
• Last Update Posted: 2011-02-15
• Primary Completion: 2011-06
• Study Completion: 2013-09

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 399

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2	Pegfilgrastim	R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2
1	ARA-C	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1	Lenograstim	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1	ASCT	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1 BIS	Vincristina	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1 BIS	ASCT	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
2 BIS	Prednisone	R-CHOP14 x 4 Restaging + R-CHOP14 x 4
1	Vincristina	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1	Rituximab	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1	Mitoxantrone	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1	Ciclofosfamide	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1	Doxorubicina	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1	Pegfilgrastim	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1	Prednisone	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1	BCNU	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1	VP-16	R-MegaCHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1 BIS	Rituximab	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1 BIS	Prednisone	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1 BIS	Pegfilgrastim	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1 BIS	ARA-C	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1 BIS	BCNU	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1 BIS	VP-16	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
2	Rituximab	R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2
1 BIS	Ciclofosfamide	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
1 BIS	Doxorubicina	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT
2	Ciclofosfamide	R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2
2	Doxorubicina	R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2
2	Vincristina	R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2
2	Prednisone	R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2
2	Mitoxantrone	R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2
2	ARA-C	R-MegaCHOP14 x 4 Restaging + R-MegaCHOP x 2
2 BIS	Rituximab	R-CHOP14 x 4 Restaging + R-CHOP14 x 4
2 BIS	Vincristina	R-CHOP14 x 4 Restaging + R-CHOP14 x 4
2 BIS	Ciclofosfamide	R-CHOP14 x 4 Restaging + R-CHOP14 x 4
2 BIS	Doxorubicina	R-CHOP14 x 4 Restaging + R-CHOP14 x 4
1 BIS	Lenograstim	R-CHOP14 x 4 Restaging + R-MAD + MAD + BEAM + ASCT

Primary Outcome Measures

Name	Time	Method
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

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

Trial Locations

Locations (74)

Ospedale Umberto I - DH Oncoematologico; 🇮🇹 Nocera Inferiore, Salerno, Italy

Ospedale Civile Umberto I; 🇮🇹 Mestre, Venezia, Italy

Osp. Calvi, Noale; 🇮🇹 Mirano, Venezia, Italy

Az. Osp. SS. Antonio e Biagio e Cesare Arrigo; 🇮🇹 Alessandria, Italy

Ospedale Cardinal Massaia; 🇮🇹 Asti, Italy

Centro di Riferimento Oncologico; 🇮🇹 Aviano - PN, Italy

Azienda Ospedale Policlinico Consorziale; 🇮🇹 Bari, Italy

IRCC Istituto tumori Ematologia; 🇮🇹 Bari, Italy

Osp. Degli Infermi; 🇮🇹 Biella, Italy

Ospedale Policlinico S. Orsola Malpighi; 🇮🇹 Bologna, Italy

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