Diffuse Large B-Cell LymphomaPhase 2CRY-04NCT01502982
Dose Dense Chemotherapy and Rituximab for Young High Risk Diffuse Large B-Cell Lymphoma Patients (CRY-04)
A Phase 2 study testing R-CHOEP14x6+HD-AraC+HD-Mtx in people with Diffuse Large B-Cell Lymphoma, run by Nordic Lymphoma Group at 4 sites in 4 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 64 years
- Conditions the study is for
- Diffuse Large B-Cell Lymphoma
- What is being tested?
- R-CHOEP14x6+HD-AraC+HD-Mtx
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 160 participants
- Where
- 4 sitesin 4 countries
- Study dates
- Nov 2004to May 2014
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 64 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
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- Previously untreated.
- Performance status < 4 (Appendix 2).
- Written informed consent
Who cannot join
- 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.
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- 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.
Trial locations and contacts
4 sites in 4 countries.
4 sites in 4 countries
About this study
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
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.
Read the 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
- Conditions
- Diffuse Large B-Cell Lymphoma
- Being tested
- R-CHOEP14x6+HD-AraC+HD-Mtx
- Keywords
- DLBCL, high risk, young
- Medical subject headings
- Lymphoma, Large B-Cell, Diffuse
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
R-CHOEP14x6+HD-AraC+HD-MtxDrug
Also called R-CHOEP14x6, HD-MTXx1, HD-AraCx1
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
| Study group | Role | What they receive |
|---|---|---|
| Chemoimmunotherapy | Experimental | Not described Receives: Drug: R-CHOEP14x6+HD-AraC+HD-Mtx |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 5 years
Secondary outcomes (6)
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
Measured: Treatment period (5 years)
Clinical response rate
Number of patients with complete and partial responses, stable or progressive disease after 3 courses and the end of treatment period
Measured: Treatment period (5 years)
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
Measured: 5 years
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.
Measured: 5 years
Incidence of CNS relapse
Measured: Treatment period (5 years)
Molecular factors important for clinical outcome
Measured: Treatment period (5 years)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Jan 2012 (estimated)
- Study startNov 2004
- Primary completionDec 2013
- Study completionMay 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Diffuse Large B-Cell LymphomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 160 participants (actual)
Sponsor and investigators
- Lead sponsor
- Nordic Lymphoma Group
- Sponsor type
- Research network
- Collaborators
- Amgen
- Responsible party
- Sponsor
- Investigators
- Harald Holte, MD, PhD, Principal investigator, Oslo University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01502982
- Sponsor's protocol ID
- NLG-LBC-04
- Other IDs
- 2004-003075-37, 2004
- Acronym
- CRY-04
- Status last verified
- Sep 2014
- First submitted
- 21 Dec 2011
- Last updated
- 30 Sep 2014
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 32079690Taskinen 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.
PubMed 24625556Holte 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.
PubMed 23247661Riihijarvi 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.
PubMed 22882209
Study at a glance
From the registry record, last updated by the sponsor on 30 Sep 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01502982
- Acronym / sponsor ID
- CRY-04 / NLG-LBC-04
- Conditions
- Diffuse Large B-Cell Lymphoma
- Keywords
- DLBCL, high risk, young
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 160 participants (actual)
- Lead sponsor
- Nordic Lymphoma GroupResearch network
- Collaborators
- Amgen
- Study start
- Nov 2004
- Primary completion
- Dec 2013 (actual)
- Study completion
- May 2014 (actual)
- First posted
- 2 Jan 2012 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Chemoimmunotherapy | Experimental | Drug: R-CHOEP14x6+HD-AraC+HD-Mtx |
Who may qualify
- Ages
- 18 to 64 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (9 listed)
- Age ≥ 18 - < 65 years.
- Histology verified according to the WHO classification and with CD20 positivity by immunhistochemistry or flow cytometry:
- 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.
Key exclusion criteria (9 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| R-CHOEP14x6+HD-AraC+HD-MtxAlso: R-CHOEP14x6, HD-MTXx1, HD-AraCx1rituximab 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 | Drug | Chemoimmunotherapy |
Primary outcome
Time to treatment failure
Time frame: 5 years
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.
6 secondary outcomes
Number of participants with adverse events
Time frame: Treatment period (5 years)
Clinical response rate
Time frame: Treatment period (5 years)
Time to progression
Time frame: 5 years
Overall survival
Time frame: 5 years
Incidence of CNS relapse
Time frame: Treatment period (5 years)
Molecular factors important for clinical outcome
Time frame: Treatment period (5 years)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Sep 2014.
- Derived from this study: PubMed 32079690Autio 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.
- Derived from this study: PubMed 24625556Taskinen 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.
- Derived from this study: PubMed 23247661Holte 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.
- Derived from this study: PubMed 22882209Riihijarvi 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.
- Nordic Lymphoma GroupLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Harald Holte, MD, PhD principal investigator
Oslo University Hospital
4 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing R-CHOEP14x6+HD-AraC+HD-Mtx in people with Diffuse Large B-Cell Lymphoma, run by Nordic Lymphoma Group at 4 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Sep 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites in Denmark, Finland, Norway, Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to treatment failure (time frame: 5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01502982, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Sep 2014.