Condition category
Cancer
Date applied
17/01/2008
Date assigned
05/02/2008
Last edited
31/05/2012
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Dr Christian Geisler

ORCID ID

Contact details

Dept. Hematology L4042
Rigshospitalet
9 Blegdamsvej
Copenhagen
DK2100
Denmark
christian.geisler@rh.regionh.dk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

N/A

Study information

Scientific title

Primary treatment with high-dose therapy and purged/unpurged autologous stem cell transplantation (ASCT), including rituximab for induction and in-vivo purging and maintenance

Acronym

Nordic MCL2 Trial

Study hypothesis

The 2nd Nordic Mantle Cell Lymphoma protocol plans to test:
1. The effect on failure-free, progression-free and overall survival of intensified induction chemotherapy, by maxi-cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), high-dose cytarabine and rituximab followed by carmustine, etoposide, cytarabine, and melphalan (BEAM)/carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC) and autologous stem cell transplant
2. The effect on the stem-cell products of in-vivo purging with rituximab 375 mg/m^2, two doses subsequent to mobilisation with high-dose cytarabine
3. The effect of further rituximab treatment post-transplant in patients with an increasing polymerase chain reaction (PCR) signal in a quantitative PCR

Ethics approval

The Scientific Ethics Committee of Copenhagen and Frederiksberg, received on the 25th April 2001 (ref: 02-008/01).

Study design

Unrandomised phase-II study

Primary study design

Interventional

Secondary study design

Non randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Mantle Cell Lymphoma

Intervention

INDUCTION:
Three series of maxi-CHOP and Ara-C and two series of rituximab:
1. Maxi-CHOP:
1.1. Cyclophosphamide (CTX) 1200 mg/m^2 day one
1.2. Doxorubicin 75 mg/m^2 day one
1.3. Vincristine 2 mg total day one
1.4. Prednisolone 100 mg total days one to five
The maxi CHOP infusions are given as bolus according to local routine. Forced diuresis and Mesna is optional.

2. High-dose Ara-C:
2.1. Patients 60 years of age or younger: Ara-C 3 g/m^2 every 12 hours for two days as 3-hour infusions (total of 4 infusions)
2.2. Patients greater than 60 years: Ara-C 2 g/m^2 every 12 hours for two days as 3-hour infusions

Supportive care including ultracortenol eyedrops should be given according to local routine. The interval between each series of maxi-CHOP and high-dose Ara-C is three weeks. Following each treatment it is recommended that, from day eight, the haematological values should be monitored regularly until the white blood cells (WBC) and platelets start to rise. Supportive treatment with haemopoietic growth factor, e.g. filgrastim 5 microgram/kg subcutaneous (s.c.) daily, during the period of neutropenia can be given according to local routine. Also prophylactic antibiotics may be given according to local routine. Dose reductions of marrow-toxic drugs may be done according to local routine, or according to the following guidelines:
2.2.1. If the leucocyte count is not at least 3 x 10^9/l or the platelet count not at least 150 x 10^9/l 21 days after the preceding course of chemotherapy, the dosages of CTX and doxorubicin or of Ara-C is reduced to 2/3 of initial dosage
2.2.2. If the leucocyte count is not at least 2 x 10^9/l or the platelet count not at least 100 x 10^9/l 21 days after the preceding course of chemotherapy, the dosages of CTX and doxorubicin or of Ara-C are reduced to 1/3 of initial dosage
2.2.3. If the leucocyte count is not at least 1.5 x 10^9/l or the platelet count not at least 75 x 10^9/l 21 days after the preceding course of chemotherapy, bone-marrow toxic therapy (CTX, doxorubicin, Ara-C is withheld until the counts rise again

3. Rituximab:
375 mg/m^2 given from cycle 2 at day one; rituximab will be given with standard infusion rates and following standard pre-treatment with paracetamol and antihistamine treatment.

STEM CELL MOBILISATION:
The third dose of HD-Ara-C is used as stem-cell mobilisation, followed from day five by filgrastim 10 microg/kg s.c. once daily.

IN-VIVO PURGING:
Rituximab 375 mg/m^2 is given at days one and nine after the start of mobilising HD-Ara-C.

STEM CELL HARVEST:
To be done according to local routine.

IN-VITRO PURGING:
Following stem-cell harvest, the fresh product may be subject to in-vitro purging according to local routine. Alternatively, the product may be frozen, while being assessed for tumour-cell contamination. If found contaminated, the product may be in-vitro purged upon thawing prior to re-infusion.

CONSOLIDATION (optional):
A fourth course of maxi-CHOP and HD-Ara-C may be given following the stem-cell harvest, depending on local circumstances (queue in transplant unit etc). If a sufficient number of stem cell is not reached after one mobilisation, the stem cell harvest may be repeated following this course of HD-ara-C. In that case, the rituximab in-vivo purging should be repeated also.

HIGH-DOSE THERAPY: BEAM OR BEAC*:
1. BEAM:
1.1. Carmustine (BCNU) 300 mg/m^2 (1-hour intravenous [i.v.] infusion) day one
1.2. Etoposide 100 mg/m^2 (1-hour i.v. infusion) every 12 hours days two to five
1.3. Ara-C 400 mg/m^2 (24-hour i.v. infusion) days two to five
1.4. Melphalan 140 mg/m^2 (1-hour i.v. infusion) day six

2. BEAC:
As BEAM, with cyclophosphamide 3000 - 6000 mg/m^2 replacing melphalan according to local routine.

*Small variations of the BEAM and BEAC regimens do occur at various centres, and the high-dose therapy should always be given according to local routine.

Filgrastim support post-transplant: Filgrastim 5 microg/kg s.c. once daily, starting day five or according to local routine.

Infection prophylaxis: Pneumocystis carinii and herpes prophylaxis is obligatory, given according to local routine. Other prophylaxis is given according to local routine.

RITUXIMAB PRE-EMPTIVE TREATMENT POST-TRANSPLANT:
Responding patients, in whom qualitative polymerase chain reaction (PCR)-negative status converts to a PCR-positive status, or in whom two serial quantitative PCR assays show increasing minimal residual disease without clinical, radiological or morphological signs of progression, should receive rituximab 375 mg/m^2 weekly for four weeks, and the PCR of blood and bone marrow repeated one month later.

The treatment lasted six months, and the duration of follow-up is to death or relapse.

Intervention type

Drug

Phase

Phase II

Drug names

CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), rituximab, BEAM (carmustine, etoposide, cytarabine, melphalan), BEAC (carmustine, etoposide, cytarabine, cyclophosphamide), autologous stem cell transplant

Primary outcome measures

Event-free survival, assessed every four months the first two years, subsequently every six months until death or relapse.

Secondary outcome measures

1. Progression free and overall survival
2. Molecular remission duration
3. Tumour-cell free stem-cell products

Assessed every four months the first two years, subsequently every six months until death or relapse.

Overall trial start date

25/04/2001

Overall trial end date

31/12/2006

Reason abandoned

Eligibility

Participant inclusion criteria

1. Newly diagnosed patients fulfilling the diagnostic criteria of Mantle Cell Lymphoma
2. Ann Arbor stage II - IV
3. 18 - 65 years of age, either sex
4. Have given informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

50

Participant exclusion criteria

Any organ dysfunction or failure that may present a risk to the patient during any phase of protocol treatment:
1. Renal function decreased corresponding to P-creatinine and/or blood urea nitrogen (BUN) increased to 2 x upper normal limit, unless clearly explained by the lymphoma
2. Liver biochemistry abnormal (P-Bilirubin, alanine aminotransferase [ALAT] or alkaline phosphatase increased to 2 x upper normal limit) unless clearly explained by the lymphoma
3. Chronic infections including human immunodeficiency virus (HIV) and hepatitis B
4. Pregnancy or lactation: for women of the childbearing age at inclusion adequate anti-conception must be secured (P-pills, depot injection gestagen or intra-uterine device)
5. Other malignancy except skin (non-melanoma) or cervix carcinoma stage 1

Recruitment start date

25/04/2001

Recruitment end date

31/12/2006

Locations

Countries of recruitment

Denmark, Finland, Norway, Sweden

Trial participating centre

Dept. Hematology L4042
Copenhagen
DK2100
Denmark

Sponsor information

Organisation

Individual sponsor (Denmark)

Sponsor details

c/o Christian Geisler
Rigshospitalet
Dept. Hematology L4042
9 Blegdamsvej
Copenhagen
DK2100
Denmark
christian.geisler@rh.regionh.dk

Sponsor type

Hospital/treatment centre

Website

http://www.rigshospitalet.dk/menu/

Funders

Funder type

Research organisation

Funder name

Nordic Cancer Union (Norway) (grant refs: 0504-D, 5-03-D, 7-05-D)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Danish Cancer Society (Denmark) (grant ref: DP 4-072)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Novo Nordisk Foundation (Novo Nordisk fonden) (Norway)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

1. 2008 results in http://www.ncbi.nlm.nih.gov/pubmed/18625886
2. 2009 results in http://www.ncbi.nlm.nih.gov/pubmed/20032504
3. 2012 results in http://www.ncbi.nlm.nih.gov/pubmed/22640180

Publication citations

  1. Results

    Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Akerman M, Ehinger M, Sundström C, Langholm R, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E, , Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group., Blood, 2008, 112, 7, 2687-2693, doi: 10.1182/blood-2008-03-147025.

  2. Results

    Geisler CH, Kolstad A, Laurell A, Räty R, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Nilsson-Ehle H, Kuittinen O, Lauritzsen GF, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E, , The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT)., Blood, 2010, 115, 8, 1530-1533, doi: 10.1182/blood-2009-08-236570.

  3. Results

    Geisler CH, Kolstad A, Laurell A, Jerkeman M, Räty R, Andersen NS, Pedersen LB, Eriksson M, Nordström M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E, , Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur., Br. J. Haematol., 2012, 158, 3, 355-362, doi: 10.1111/j.1365-2141.2012.09174.x.

Additional files

Editorial Notes