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

Sponsor

Nordic Lymphoma Group (Other)

Overall Status

Completed

CT.gov ID

NCT01502982

Collaborator

Amgen (Industry)

160

Enrollment

Locations

Arm

113.9

Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-Cell Lymphoma	Drug: R-CHOEP14x6+HD-AraC+HD-Mtx	Phase 2

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

Study Type:

Interventional

Actual Enrollment :

160 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Nov 1, 2004

Actual Primary Completion Date :

Dec 1, 2013

Actual Study Completion Date :

May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Chemoimmunotherapy	Drug: R-CHOEP14x6+HD-AraC+HD-Mtx 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 Other Names: R-CHOEP14x6 HD-MTXx1 HD-AraCx1

Arm

Intervention/Treatment

Experimental: Chemoimmunotherapy

Drug: R-CHOEP14x6+HD-AraC+HD-Mtx

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

Other Names:

R-CHOEP14x6

HD-MTXx1

HD-AraCx1

Outcome Measures

Primary Outcome Measures

Time to treatment failure [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.

Secondary Outcome Measures

Number of participants with adverse events [Treatment period (5 years)]
Grade 2-4 hematological and non-hematological adverse events according to the WHO Common Toxicity Criteria as specified in the protocol
Clinical response rate [Treatment period (5 years)]
Number of patients with complete and partial responses, stable or progressive disease after 3 courses and the end of treatment period
Time to progression [5 years]
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 [5 years]
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 [Treatment period (5 years)]
Molecular factors important for clinical outcome [Treatment period (5 years)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 64 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country
1	Odense University Hospital	Odense	Denmark
2	Helsinki University central Hospital	Helsinki	Finland
3	Oslo University Hospital	Oslo	Norway
4	Lund University Hospital	Lund	Sweden