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Dose Dense Chemotherapy and Rituximab for Young High Risk Diffuse Large B-Cell Lymphoma Patients (CRY-04) (CRY-04)

Primary Purpose

Diffuse Large B-Cell Lymphoma

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
R-CHOEP14x6+HD-AraC+HD-Mtx
Sponsored by
Nordic Lymphoma Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Large B-Cell Lymphoma focused on measuring DLBCL, high risk, young

Eligibility Criteria

18 Years - 64 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age ≥ 18 - < 65 years.

  2. Histology verified according to the WHO classification and with CD20 positivity by immunhistochemistry or flow cytometry:

    • Diffuse large B-cell lymphomas with subgroups except posttransplantation-, Burkitt-like- and primary CNS lymphomas and cases with leptomeningeal lymphoma involvement. Morphologically discordant lymphomas (most often follicular lymphoma and diffuse large cell B-cell lymphoma in different biopsy specimens, e.g. lymphatic gland and bone marrow) and transformed lymphomas are not to be included.
    • Follicular lymphomas grade III The diagnosis made by the local pathologist of the participating centre will be accepted for registration

  3. Patients in at least stage II with age adjusted IPI score of 2 or 3:

    Stage III /IV and elevated LDH and/or WHO performance status 2 - 3 Stage II and elevated LDH and WHO performance status 2 - 3.

  4. Previously untreated.
  5. Performance status < 4 (Appendix 2).
  6. Written informed consent

Exclusion Criteria:

  1. Severe cardiac disease: cardiac function grade 3-4 (Appendix 2) or Left Ventricular Ejection Fraction (LVEF) < 45% (based on MUGA scintigraphy or echo Doppler cardiography).
  2. Impaired liver, renal or other organ function not caused by lymphoma, which will interfere with the treatment schedule.
  3. Pregnancy.
  4. Men and women of reproductive potential not agreeing to use an acceptable method of birth control during treatment and for six months after completion of treatment.
  5. Patients with other severe medical problems and with an expected short survival for non-lymphoma reasons.
  6. Known HIV positivity.
  7. Present or previous cancer except basal cell carcinoma and cervical carcinoma in situ.
  8. Uncontrolled infectious disease.
  9. Psychiatric or mental disorder which make the patient unable to give an informed consent and/or adhere to the protocol.

Sites / Locations

  • Odense University Hospital
  • Helsinki University central Hospital
  • Oslo University Hospital
  • Lund University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Chemoimmunotherapy

Arm Description

Outcomes

Primary Outcome Measures

Time to treatment failure
Interval between the registration date and the date of documented progression or lack of response, first relapse, death for any reason or discontinuation/change of therapy because of toxicity, whichever occurs first. Otherwise, patients will be censored at the last date they were known to be alive. For patients not responding at any time point on study treatment, TTF is defined as 1 day.

Secondary Outcome Measures

Number of participants with adverse events
Grade 2-4 hematological and non-hematological adverse events according to the WHO Common Toxicity Criteria as specified in the protocol
Clinical response rate
Number of patients with complete and partial responses, stable or progressive disease after 3 courses and the end of treatment period
Time to progression
Time from registration to the date of disease progression. Otherwise, the patients are censored at the last date of follow up. Patients still alive in a complete response or lost to follow-up are censored at the last date they were known to be alive. Patients who die due to causes other than lymphoma are censored at the date of death
Overall survival
Time from the registration date to the date of death. Patients still alive or lost to follow-up are censored at the last date they were known to be alive.
Incidence of CNS relapse
Molecular factors important for clinical outcome

Full Information

First Posted
December 21, 2011
Last Updated
September 27, 2014
Sponsor
Nordic Lymphoma Group
Collaborators
Amgen
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1. Study Identification

Unique Protocol Identification Number
NCT01502982
Brief Title
Dose Dense Chemotherapy and Rituximab for Young High Risk Diffuse Large B-Cell Lymphoma Patients (CRY-04)
Acronym
CRY-04
Official Title
CHOEP-14 + Rituximab With CNS Prophylaxis in Patients Less Than 65 Years With Diffuse Large B-Cell Lymphoma/Follicular Lymphoma Grade III, Stage II-IV With Risk Factors (Age Adjusted IPI) ≥ 2. A Phase II Study
Study Type
Interventional

2. Study Status

Record Verification Date
September 2014
Overall Recruitment Status
Completed
Study Start Date
November 2004 (undefined)
Primary Completion Date
December 2013 (Actual)
Study Completion Date
May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Nordic Lymphoma Group
Collaborators
Amgen

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose is to test whether dose densified chemoimmunotherapy followed by central nervous system (CNS) prophylaxis for young high risk diffuse large B-cell lymphoma (DLBCL) patients is feasible and could improve time to treatment failure and reduce the risk of CNS relapses. Six courses of rituximab-cyclophosphamide-doxorubicin-etoposide-vincristine-prednison (R-CHOEP) given in two weeks intervals with the support of G-CSF is followed by one course of high dose methotrexate (HD-MTX) and high dose cytarabine (HD-Ara-C). The results will be compared to a historical Nordic study.
Detailed Description
Pathology: Patients may be included on the bases of the histological diagnosis of the local pathologist. The specimen will be reviewed by a central pathologist in each country Treatment: All patients receive CHOEP-14 with rituximab x 6 with the support of G-CSF followed by high dose cytarabine i.v. and high dose methotrexate i.v.Intrathecal (i.t.) CNS prophylaxis in combination with chemotherapy is not to be given, but i.t. methotrexate may be given once after initial liquid sampling. Radiotherapy will be given at the discretion of the individual centres. Investigations before, during and after treatment: The disease status will be assessed prior to treatment start, after 3 cycles of CHOEP + rituximab and after completion of the treatment schedule. Positron Emission Tomography (PET) using F18 deoxyglucose may be performed after fulfillment of treatment. Persistent, suspected lymphoma tissue should whenever possible be confirmed with a biopsy, otherwise the patient will be regarded as PR and second line therapy will be considered (see schematic outline). Clinical and radiological (CT) assessment are performed at pretreatment and subsequently on sites initially involved, and bone marrow biopsy if initially involved After the 3rd course After the last course (within one month) of chemotherapy (biopsy if indicated) After radiotherapy (for patient given radiotherapy as part of the primary treatment) Clinical follow-up: 4x per year during the first and second year of follow-up 2x per year during the third, fourth and fifth year of follow-up Radiological investigations at follow up: -CT after 6, 12 and 24 months of sites initially involved. CT abdomen in all cases after 12 and 24 months. X-ray of the thorax (if CT thorax is performed) after 6, 12 and 24 months

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Large B-Cell Lymphoma
Keywords
DLBCL, high risk, young

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
160 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Chemoimmunotherapy
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
R-CHOEP14x6+HD-AraC+HD-Mtx
Other Intervention Name(s)
R-CHOEP14x6, HD-MTXx1, HD-AraCx1
Intervention Description
rituximab 375 mg/m2 day 1 cyclophosphamide 750 mg/m2 day 1 doxorubicin 50 mg/m2 day 1 vincristine 1.4 mg/m2 day 1 etoposide 100mg/m2 days 1,2,3 Prednison 100 mg days 1,2,3,4,5 cycle repeated six times every two weeks followed by HD-AraC 3g/m2x4 and HD-mtx 3 g/m2 HD-AraC 3g/m2x4 times every 12 h
Primary Outcome Measure Information:
Title
Time to treatment failure
Description
Interval between the registration date and the date of documented progression or lack of response, first relapse, death for any reason or discontinuation/change of therapy because of toxicity, whichever occurs first. Otherwise, patients will be censored at the last date they were known to be alive. For patients not responding at any time point on study treatment, TTF is defined as 1 day.
Time Frame
5 years
Secondary Outcome Measure Information:
Title
Number of participants with adverse events
Description
Grade 2-4 hematological and non-hematological adverse events according to the WHO Common Toxicity Criteria as specified in the protocol
Time Frame
Treatment period (5 years)
Title
Clinical response rate
Description
Number of patients with complete and partial responses, stable or progressive disease after 3 courses and the end of treatment period
Time Frame
Treatment period (5 years)
Title
Time to progression
Description
Time from registration to the date of disease progression. Otherwise, the patients are censored at the last date of follow up. Patients still alive in a complete response or lost to follow-up are censored at the last date they were known to be alive. Patients who die due to causes other than lymphoma are censored at the date of death
Time Frame
5 years
Title
Overall survival
Description
Time from the registration date to the date of death. Patients still alive or lost to follow-up are censored at the last date they were known to be alive.
Time Frame
5 years
Title
Incidence of CNS relapse
Time Frame
Treatment period (5 years)
Title
Molecular factors important for clinical outcome
Time Frame
Treatment period (5 years)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
64 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 18 - < 65 years. Histology verified according to the WHO classification and with CD20 positivity by immunhistochemistry or flow cytometry: Diffuse large B-cell lymphomas with subgroups except posttransplantation-, Burkitt-like- and primary CNS lymphomas and cases with leptomeningeal lymphoma involvement. Morphologically discordant lymphomas (most often follicular lymphoma and diffuse large cell B-cell lymphoma in different biopsy specimens, e.g. lymphatic gland and bone marrow) and transformed lymphomas are not to be included. Follicular lymphomas grade III The diagnosis made by the local pathologist of the participating centre will be accepted for registration Patients in at least stage II with age adjusted IPI score of 2 or 3: Stage III /IV and elevated LDH and/or WHO performance status 2 - 3 Stage II and elevated LDH and WHO performance status 2 - 3. Previously untreated. Performance status < 4 (Appendix 2). Written informed consent Exclusion Criteria: Severe cardiac disease: cardiac function grade 3-4 (Appendix 2) or Left Ventricular Ejection Fraction (LVEF) < 45% (based on MUGA scintigraphy or echo Doppler cardiography). Impaired liver, renal or other organ function not caused by lymphoma, which will interfere with the treatment schedule. Pregnancy. Men and women of reproductive potential not agreeing to use an acceptable method of birth control during treatment and for six months after completion of treatment. Patients with other severe medical problems and with an expected short survival for non-lymphoma reasons. Known HIV positivity. Present or previous cancer except basal cell carcinoma and cervical carcinoma in situ. Uncontrolled infectious disease. Psychiatric or mental disorder which make the patient unable to give an informed consent and/or adhere to the protocol.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Harald Holte, MD, PhD
Organizational Affiliation
Oslo University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Odense University Hospital
City
Odense
Country
Denmark
Facility Name
Helsinki University central Hospital
City
Helsinki
Country
Finland
Facility Name
Oslo University Hospital
City
Oslo
Country
Norway
Facility Name
Lund University Hospital
City
Lund
Country
Sweden

12. IPD Sharing Statement

Citations:
PubMed Identifier
32079690
Citation
Autio M, Leivonen SK, Bruck O, Mustjoki S, Meszaros Jorgensen J, Karjalainen-Lindsberg ML, Beiske K, Holte H, Pellinen T, Leppa S. Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma. Haematologica. 2021 Mar 1;106(3):718-729. doi: 10.3324/haematol.2019.243626.
Results Reference
derived
PubMed Identifier
24625556
Citation
Taskinen M, Louhimo R, Koivula S, Chen P, Rantanen V, Holte H, Delabie J, Karjalainen-Lindsberg ML, Bjorkholm M, Fluge O, Pedersen LM, Fjorden K, Jerkeman M, Eriksson M, Hautaniemi S, Leppa S. Deregulation of COMMD1 is associated with poor prognosis in diffuse large B-cell lymphoma. PLoS One. 2014 Mar 13;9(3):e91031. doi: 10.1371/journal.pone.0091031. eCollection 2014.
Results Reference
derived
PubMed Identifier
23247661
Citation
Holte H, Leppa S, Bjorkholm M, Fluge O, Jyrkkio S, Delabie J, Sundstrom C, Karjalainen-Lindsberg ML, Erlanson M, Kolstad A, Fossa A, Ostenstad B, Lofvenberg E, Nordstrom M, Janes R, Pedersen LM, Anderson H, Jerkeman M, Eriksson M. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol. 2013 May;24(5):1385-92. doi: 10.1093/annonc/mds621. Epub 2012 Dec 17.
Results Reference
derived
PubMed Identifier
22882209
Citation
Riihijarvi S, Nurmi H, Holte H, Bjorkholm M, Fluge O, Pedersen LM, Rydstrom K, Jerkeman M, Eriksson M, Leppa S. High serum vascular endothelial growth factor level is an adverse prognostic factor for high-risk diffuse large B-cell lymphoma patients treated with dose-dense chemoimmunotherapy. Eur J Haematol. 2012 Nov;89(5):395-402. doi: 10.1111/ejh.12005. Epub 2012 Sep 14.
Results Reference
derived
Links:
URL
http://www.nordic-lymphoma.org/
Description
Nordic Lymphoma Group

Learn more about this trial

Dose Dense Chemotherapy and Rituximab for Young High Risk Diffuse Large B-Cell Lymphoma Patients (CRY-04)

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