R-MCEB: R-MegaCHOP-ESHAP-BEAM in Patients With High-Risk Aggressive B-Cell Lymphomas

Sponsor

Czech Lymphoma Study Group (Other)

Overall Status

Completed

CT.gov ID

NCT00558220

Collaborator

Ministry of Health, Czech Republic (Other), Hoffmann-La Roche (Industry)

106

Enrollment

Locations

Arm

Duration (Months)

13.3

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to show if addition of Rituximab to intensive induction (MegaCHOP/ESHAP) and high-dose consolidation (BEAM) improves progression-free and overall survival in patients younger than 65 years with aggressive B-cell lymphoma and aaIPI 2 or 3.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-Cell Lymphoma. Primary Mediastinal B-Cell Lymphoma Follicular Lymphoma Grade III	Procedure: immunotherapy Procedure: Induction treatment part 1 Procedure: Induction treatment part 2 with PBPC collection Procedure: Induction treatment part 3 Procedure: Consolidation treatment part 1: HD-chemotherapy with ASCT Radiation: Consolidation treatment part 2: Radiotherapy	Phase 2

Detailed Description

Previous study of Czech Lymphoma Study Group (4_2002)have shown that intensive induction (MegaCHOP - Cyclophosphamide 3 g/m2, Vincristine 2 mg, Adriamycin 75 mg/m2, Prednisone 300 mg/m2 every three weeks with G-CSF for three cycles, followed by ESHAP - Etoposide 240 mg/m2, Cisplatin 100 mg/m2, Solumedrol 2000 mg and cytarabine 2000 mg/m2 for three cycles every three weeks with G-CSF) followed by intensive consolidation (BEAM) and stem cell support improves progression-free survival in adult patients (18-65 years old) with aggressive B-cell lymphoma (namely, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma and follicular lymphoma grade II) with aaIPI 2 and namely, with aaIPI 3. This study was aimed to find out if addition of four to six doses of Rituximab 375 mg/m2 on first day of every cycle of intensive induction further improves prognosis of these patients.

Inclusion criteria for this trial were:

newly diagnosed aggressive B-cell lymphoma, namely diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma and follicular lymphoma grade III
age 18-65 years
age adjusted IPI (International Prognostic Index) score 2 or 3
ECOG performance status 0-3
signed informed consent

Exclusion criteria were:

relapsed lymphoma
previous treatment (up to one cycle of standard pretreatment - COP, CHOP or steroids was permitted and later became mandatory to decrease disease burden and/or improve the performance status of the patient)
Burkitt lymphoma
posttransplant lymphoproliferation
CNS involvement
other malignant tumor in previous history, except basalioma, skin squamocellular carcinoma or cervical carcinoma in situ
other serious comorbidity

Primary endpoints was progression-free survival

Secondary endpoints were:

rate of complete remission and overall response rate
overall survival
toxicity of the protocol, measured as grade III-IV toxicity and/or inability to finish the protocol as planned

Planned number of accrued patients was 100.

Study Design

Study Type:

Interventional

Actual Enrollment :

106 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase II Study of Intensive Induction (R-MegaCHOP/ESHAP)Followed By Intensive Consolidation (BEAM) In Treatment Of High-Risk Aggressive B-Cell Lymphomas

Study Start Date :

May 1, 2002

Actual Study Completion Date :

Oct 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A Intensive induction followed by high-dose consolidation with stem cell support ± radiotherapy	Procedure: immunotherapy Given together with induction chemotherapy: Rituximab - 375 mg/m2 iv every 3 weeks, 4-6 doses Procedure: Induction treatment part 1 cyclophosphamide 3000 mg/m2 iv every 3 weeks, 3 cycles vincristin 2 mg iv every 3 weeks, 3 cycles doxorubicin 75 mg/m2 iv every 3 weeks, 3 cycles Prednisolone 300 mg/m2 divided into five days po every 3 weeks, 3 cycles pegfilgrastim 6 mg sc every 3 weeks. 3 cycles consisting of combination treatment of above mentioned drugs are given. Procedure: Induction treatment part 2 with PBPC collection Starts three weeks after last cycle of Induction part 1. Etoposide 240 mg/m2 divided into equal doses for four days, together with methylprednisolone 2000 mg divided into equal doses for four days, together with cisplatin 100 mg/m2 divided into equal doses for four days, and together with cytarabine 2000 mg/m2 iv one dose on 4th day of treatment. Filgrastim 10-12 ug/kg from day five after start of chemotherapy untill stem cell collection. Peripheral blood progenitor cell collection (PBPC) is started when CD34 positive cells are >20/cubic milimeter of blood and continued untill 5 million of CD34 positive cells are collected from peripheral blood. Procedure: Induction treatment part 3 Part 3 of induction treatment is given approximately one week after the end of Part 2. Etoposide 240 mg/m2 divided into equal doses for four days, methylprednisolone 2000 mg divided into equal doses for four days, cisplatin 100 mg/m2 divided into equal doses for four days, cytarabine 2000 mg/m2 iv one dose on day 4 of chemotherapy and pegfilgrastim 6 mg on day five of chemotherapy are given twice three weeks apart. Procedure: Consolidation treatment part 1: HD-chemotherapy with ASCT Consolidation treatment Part 1 starts 4-8 weeks after the second cycle of Induction treatment Part 3. High dose chemotherapy (HD-chemotherapy) consists of: BCNU 300 mg/m2 is given on day 1, etoposide 800 mg/m2 divided into four equal doses is given on day 2-5, cytarabine 1600 mg/m2 divided into eight equal doses is given on day 2-5, melphalan 140 mg/m2 is given on day 6. On day 7, collected stem cells from peripheral blood (see Induction treatment part 1) are infused back to the patient. This is called autologous transplantation (ASCT). Filgrastim 5 ug/kg is given from day 14 (start of the chemotherapy being day 1) until neutrophil recovery. Radiation: Consolidation treatment part 2: Radiotherapy Radiotherapy is started given 4-8 weeks after the autologous transplantation. It is given to patients with initially bulky disease (>10 cm at diagnosis) or to patients with residual disease after Induction treatment part 1-3 and Consolidation treatment part 1. 30-40 Gy are given in 2 Gy fractions over 3-4 weeks.

Arm

Intervention/Treatment

Experimental: A

Intensive induction followed by high-dose consolidation with stem cell support ± radiotherapy

Procedure: immunotherapy

Given together with induction chemotherapy: Rituximab - 375 mg/m2 iv every 3 weeks, 4-6 doses

Procedure: Induction treatment part 1

cyclophosphamide 3000 mg/m2 iv every 3 weeks, 3 cycles vincristin 2 mg iv every 3 weeks, 3 cycles doxorubicin 75 mg/m2 iv every 3 weeks, 3 cycles Prednisolone 300 mg/m2 divided into five days po every 3 weeks, 3 cycles pegfilgrastim 6 mg sc every 3 weeks. 3 cycles consisting of combination treatment of above mentioned drugs are given.

Procedure: Induction treatment part 2 with PBPC collection

Starts three weeks after last cycle of Induction part 1. Etoposide 240 mg/m2 divided into equal doses for four days, together with methylprednisolone 2000 mg divided into equal doses for four days, together with cisplatin 100 mg/m2 divided into equal doses for four days, and together with cytarabine 2000 mg/m2 iv one dose on 4th day of treatment. Filgrastim 10-12 ug/kg from day five after start of chemotherapy untill stem cell collection. Peripheral blood progenitor cell collection (PBPC) is started when CD34 positive cells are >20/cubic milimeter of blood and continued untill 5 million of CD34 positive cells are collected from peripheral blood.

Procedure: Induction treatment part 3

Part 3 of induction treatment is given approximately one week after the end of Part 2. Etoposide 240 mg/m2 divided into equal doses for four days, methylprednisolone 2000 mg divided into equal doses for four days, cisplatin 100 mg/m2 divided into equal doses for four days, cytarabine 2000 mg/m2 iv one dose on day 4 of chemotherapy and pegfilgrastim 6 mg on day five of chemotherapy are given twice three weeks apart.

Procedure: Consolidation treatment part 1: HD-chemotherapy with ASCT

Consolidation treatment Part 1 starts 4-8 weeks after the second cycle of Induction treatment Part 3. High dose chemotherapy (HD-chemotherapy) consists of: BCNU 300 mg/m2 is given on day 1, etoposide 800 mg/m2 divided into four equal doses is given on day 2-5, cytarabine 1600 mg/m2 divided into eight equal doses is given on day 2-5, melphalan 140 mg/m2 is given on day 6. On day 7, collected stem cells from peripheral blood (see Induction treatment part 1) are infused back to the patient. This is called autologous transplantation (ASCT). Filgrastim 5 ug/kg is given from day 14 (start of the chemotherapy being day 1) until neutrophil recovery.

Radiation: Consolidation treatment part 2: Radiotherapy

Radiotherapy is started given 4-8 weeks after the autologous transplantation. It is given to patients with initially bulky disease (>10 cm at diagnosis) or to patients with residual disease after Induction treatment part 1-3 and Consolidation treatment part 1. 30-40 Gy are given in 2 Gy fractions over 3-4 weeks.

Outcome Measures

Primary Outcome Measures

Progression-free survival [3 years]

Secondary Outcome Measures

Complete remission and overall response rate [One year]
Overall survival [3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Aggressive B-cell lymphoma, namely diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, follicular lymphoma grade III
Age 18-65 years
Age-adjusted IPI score 2-3
ECOG performance status 0-3
Signed informed consent

Exclusion Criteria:

Burkitt lymphoma
Posttransplant lymphoproliferation
Previous treatment (up to one cycle of standard pretreatment with COP, CHOP or steroids permitted and latter mandatory to decrease tumor burden and/or improve performance status)
Other tumor in previous history with the exception of basalioma, squamous cell carcinoma of the skin or cervical carcinoma in situ
Pregnancy/lactation
CNS involvement
Other serious comorbidities

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	University Hospital Brno-Bohunice	Brno	Czech Republic	625 00
2	Hospital Chomutov	Chomutov	Czech Republic	430 12
3	University Hospital Hradec Králové	Hradec Králové	Czech Republic	500 05
4	University Hospital Královské Vinohrady	Prague	Czech Republic	100 34
5	General University Hospital	Prague	Czech Republic	128 08
6	University Hospital Motol	Prague	Czech Republic	150 00
7	Hospital Ústí nad Labem	Usti nad Labem	Czech Republic	401 13
8	Hospital České Budějovice	České Budějovice	Czech Republic

Sponsors and Collaborators

Czech Lymphoma Study Group
Ministry of Health, Czech Republic
Hoffmann-La Roche

Investigators

Principal Investigator: Pytlik Robert, M.D., 1st Department of Medicine, General University Hospital, Prague
Study Director: Marek Trněný, M.D., PhD., General University Hospital, Prague