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Phase III study comparing R-CODOX-M/R-IVAC versus dose-adjusted EPOCH-R (DA-EPOCH-R) for patients with newly diagnosed high risk Burkitt lymphoma


- candidate number17854
- NTR NumberNTR4602
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR20-mei-2014
- Secondary IDsHO127 HOVON
- Public TitlePhase III study comparing R-CODOX-M/R-IVAC versus dose-adjusted EPOCH-R (DA-EPOCH-R) for patients with newly diagnosed high risk Burkitt lymphoma
- Scientific TitlePhase III study comparing R-CODOX-M/R-IVAC versus dose-adjusted EPOCH-R (DA-EPOCH-R) for patients with newly diagnosed high risk Burkitt lymphoma
- ACRONYMHOVON 127 BL
- hypothesisThe hypothesis to be tested is that the outcome in arm B is better than in arm A.
- Healt Condition(s) or Problem(s) studiedNon Hodkin's lymfoma (NHL), Burkitt lymphoma
- Inclusion criteria- First diagnosis of high risk Burkitt lymphoma (sporadic and HIV associated), histologically confirmed according to the WHO classification 2008;
- High risk disease; i.e. any of following: elevated LDH, WHO performance status > 2, Ann Arbor stage III or IV, tumour mass > 10 cm;
- Age 18-75 years inclusive;
- WHO performance status (PS) 0-3, WHO PS 4 only if disease related;
- Written informed consent.
- Exclusion criteria- All histopathological diagnoses other than Burkitt lymphoma according to the WHO classification 2008, irrespective of the presence of a MYC rearrangement;
- Patients with endemic Burkitt lymphoma;
- Patients with low risk Burkitt lymphoma (i.e. all of following: normal LDH, WHO performance status 0 or 1, Ann Arbor stage I or II, no tumour mass °› 10 cm);
- Patients with CNS localization of Burkitt lymphoma;
- Prior treatment other than local radiation (max. 10 Gy) or short course (max 7 days) of steroids °‹ 1 mg/kg for acute symptoms;
- Creatinine clearance < 50 ml/min unless lymphoma related;
- Inadequate hepatic function: bilirubin > 2.5 * ULN (total) except patients with Gilbert°Įs syndrome as defined by > 80% unconjugated;
- Inadequate hematological function ANC < 1x10^9/l and platelets < 75x10^9 /l unless lymphoma related;
- Severe pulmonary dysfunction (CTCAE grade 3-4);
- Severe neurological or psychiatric disease;
- Active symptomatic ischemic heart disease, myocardial infarction, or congestive heart failure within the past year. If an ultrasound or MUGA scan is obtained the LVEF should exceed 45%;
- All men and all women of child-bearing potential not willing or able to use an acceptable method of birth control for the duration of the study and one year beyond treatment completion;
- Female subject pregnant or breast-feeding;
- History of a prior invasive malignancy in the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
- Serious concomitant medical illnesses that would jeopardize the patient's ability to receive the regimen with reasonable safety, including active hepatitis B (HBV) or hepatitis C (HCV) infection or history of HBV infection (patients with serological evidence of current or past HBV exposure are excluded unless the serological findings are clearly due to vaccination);
- Current participation in another clinical trial;
- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 15-jun-2014
- planned closingdate15-jun-2025
- Target number of participants260
- InterventionsArm A: R-CODOX-M/R-IVAC
2 cycles of R-CODOX-M and 2 cycles R-IVAC
(alternately) total of 16 weeks (4 weeks per cycle) R-CODOX-M consists of:
- rituximab i.v. (day 1,9: 375 mg/m^2/d)
- cyclophosphamide i.v. (day 1: 800 mg/m^2, day 2-5: 200 mg/m^2/d)
- vincristine i.v. (day 1,8: 1.5 mg/d)
- doxorubicin i.v. (day 1: 40 mg/m^2)
- methotrexate i.v.(day 10: 3000 mg/m^2 (<= 65 y), 1000 mg/m^2 (> 65 y))

R-IVAC consists of:
- rituximab i.v. (day 3,7: 375 mg/m^2/d)
- ifosfamide (day 1-5: 1500 mg/m^2/d (<=65 y), 1000 mg/m^2/d (>65 y))
- etoposide i.v. (day 1-5: 60 mg/m^2/d)
- cytarabine i.v. (day 1,2: 4000 mg/^2/d (<=65 y), 2000 mg/m^2/d (>65 y)

Both regimens also include supportive care and i.t. prophylaxis.

Arm B: DA-EPOCH-R
6 cycles, 3 weeks per cycle, total of 18 weeks
- etoposide i.v. (day 1-4: 50-124.4 mg/m^2/d continuous infusion, dose adjustment possible at every cycle)
- prednisolone p.o. (day 1-5 : 120 mg/m^2/d)
- vincristine i.v. (day 1-4: 0.4 mg/m^2/d continuous infusion)
- cyclophosphamide i.v. (day 5: 480-1866 mg/m^2/d dose adjustment possible at every cycle)
- doxorubicin i.v. (day 1-4 : 10-24.8 mg/m^2/d continuous infusion, dose adjustment possible at every cycle)
- rituximab i.v. (day 1,5: 375 mg/m^/d)
Also with supportive care and i.t. prophylaxis.
- Primary outcome2 years EFS; time from registration to first event (death from any cause, no CR, relapse, whichever comes first). Patients still alive or lost to follow up are censored at the date they were last known to be alive
- Secondary outcome- Overall Response Rate at end-of-treatment
- Overall Survival at 2 years; defined as time from registration until death from any cause; patients still alive or lost to follow up are censored at the date they were last known to be alive
- Rate of CTCAE grade >=3 toxicities
- Number of hospitalization days versus days in an outpatient setting
- TimepointsAt entry, at mid treatment (after cycle 2 in arm A, after cycle 3 in arm B), at end of treatment, during follow-up (every 3 months until 6 months after completion of therapy, then every 6 months until 24 months after therapy, and then annually until 5 years after registration)
- Trial web sitewww.hovon.nl
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESDr. M.E.D. Chamuleau
- CONTACT for SCIENTIFIC QUERIESDr. M.E.D. Chamuleau
- Sponsor/Initiator Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON)
- Funding
(Source(s) of Monetary or Material Support)
Stichting Hemato-Oncologie voor Volwassenen Nederland (HOVON), KWF Kankerbestrijding
- PublicationsNot yet for this trial.
- Brief summaryStudy phase: phase III
Study objectives:
Primary objective
- To confirm in a multicenter setting an improvement in PFS to 85% at 2 years of DA-EPOCH-R in patients with newly diagnosed high risk Burkitt lymphoma as compared to an expected PFS of 70% at 2 years for the control arm R-CODOX-M/R-IVAC.
Secondary objectives:
- To evaluate Overall Response Rate (ORR) end-of-treatment, Event Free Survival (EFS) and Overall Survival (OS) at 2 years - To evaluate both regimens with respect to CTCAE grade ≥3 toxicity
- To evaluate both regimens with respect to hospitalisation days
Patient population: Patients with newly diagnosed high risk Burkitt lymphoma 18 -75 years
Study design: prospective, multi-center, randomized
Duration of treatment: Arm A: 16 weeks, Arm B: 18 weeks
- Main changes (audit trail)11-nov-2017 -IK:

Inclusion criteria:

- First diagnosis of high risk Burkitt lymphoma (sporadic and HIV associated), histologically confirmed according to the WHO classification 2008;
- High risk disease; i.e. any of following: elevated LDH, WHO performance status > 2, Ann Arbor stage III or IV, tumour mass > 10 cm;
- Age 18-75 years inclusive;
- WHO performance status (PS) 0-3, WHO PS 4 only if disease related;
- Written informed consent.

replaced by

- First diagnosis of high risk Burkitt lymphoma (sporadic and HIV associated), histologically confirmed according to the WHO classification 2008. Upon its availability the WHO 2016 classification should be used, to replace the WHO 2008 classification;
- High risk disease; i.e. any of following: elevated LDH, WHO performance status ≥ 2, Ann Arbor stage III or IV, tumour mass ≥ 10 cm;
- Age 18-75 years inclusive;
- WHO performance status (PS) 0-3, WHO PS 4 only if disease related;
- Written informed consent.


Exclusion criteria:

- All histopathological diagnoses other than Burkitt lymphoma according to the WHO classification 2008, irrespective of the presence of a MYC rearrangement;
- Patients with endemic Burkitt lymphoma;
- Patients with low risk Burkitt lymphoma (i.e. all of following: normal LDH, WHO performance status 0 or 1, Ann Arbor stage I or II, no tumour mass °› 10 cm);
- Patients with CNS localization of Burkitt lymphoma;
- Prior treatment other than local radiation (max. 10 Gy) or short course (max 7 days) of steroids °‹ 1 mg/kg for acute symptoms;
- Creatinine clearance < 50 ml/min unless lymphoma related;
- Inadequate hepatic function: bilirubin > 2.5 * ULN (total) except patients with Gilbert°Įs syndrome as defined by > 80% unconjugated;
- Inadequate hematological function ANC < 1x10^9/l and platelets < 75x10^9 /l unless lymphoma related;
- Severe pulmonary dysfunction (CTCAE grade 3-4);
- Severe neurological or psychiatric disease;
- Active symptomatic ischemic heart disease, myocardial infarction, or congestive heart failure within the past year. If an ultrasound or MUGA scan is obtained the LVEF should exceed 45%;
- All men and all women of child-bearing potential not willing or able to use an acceptable method of birth control for the duration of the study and one year beyond treatment completion;
- Female subject pregnant or breast-feeding;
- History of a prior invasive malignancy in the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
- Serious concomitant medical illnesses that would jeopardize the patient's ability to receive the regimen with reasonable safety, including active hepatitis B (HBV) or hepatitis C (HCV) infection or history of HBV infection (patients with serological evidence of current or past HBV exposure are excluded unless the serological findings are clearly due to vaccination);
- Current participation in another clinical trial;
- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

replaced by

- All histopathological diagnoses other than Burkitt lymphoma according to the WHO classification 2008, irrespective of the presence of a MYC rearrangement. Upon its availability the WHO 2016 classification should be used, to replace the WHO 2008 classification;
- Patients with endemic Burkitt lymphoma;
- Patients with low risk Burkitt lymphoma (i.e. all of following: normal LDH, WHO performance status 0 or 1, Ann Arbor stage I or II, no tumour mass ≥ 10 cm);
- Patients with CNS localisation of Burkitt lymphoma;
- Prior treatment other than local radiation (max. 10 Gy) or short course (max 7 days) of steroids ≤ 1 mg/kg or ≤100mg prednisolone (whichever is greater; or equivalent corticosteroid) for acute symptoms;
- Creatinine clearance < 50 ml/min unless lymphoma related;
- Inadequate hepatic function: bilirubin > 2.5 * ULN (total) except patients with Gilbertís syndrome as defined by > 80% unconjugated;
- Inadequate haematological function ANC < 1x10^9/l and platelets < 75x10^9 /l unless lymphoma related;
- Severe pulmonary dysfunction (CTCAE grade 3-4);
- Severe neurological or psychiatric disease;
- Active symptomatic ischemic heart disease, myocardial infarction, or congestive heart failure within the past year. If an ultrasound or MUGA scan is obtained the LVEF should exceed 45%;
- All men and all women of child-bearing potential not willing or able to use an acceptable method of birth control for the duration of the study and one year beyond treatment completion;
- Female subject pregnant or breast-feeding;
- History of a prior invasive malignancy in the past 5 years with the exception of basal carcinoma of the skin or stage 0 cervical carcinoma;
- Serious concomitant medical illnesses that would jeopardise the patient's ability to receive the regimen with reasonable safety, including active hepatitis B (HBV) or hepatitis C (HCV) infection;
- Current participation in another clinical trial if interfering with HO127;
- Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.


Primary outcome:
2 years EFS; time from registration to first event (death from any cause, no CR, relapse, whichever comes first). Patients still alive or lost to follow up are censored at the date they were last known to be alive

replaced by

2 year PFS; defined as time from randomisation to disease progression, relapse or death, whichever comes first. Patients still alive or lost to follow up are censored at the date they were last known to be alive


Secondary outcome:

- Overall Response Rate at end-of-treatment
- Overall Survival at 2 years; defined as time from registration until death from any cause; patients still alive or lost to follow up are censored at the date they were last known to be alive
- Rate of CTCAE grade >=3 toxicities
- Number of hospitalization days versus days in an outpatient setting

replaced by

- ORR end-of-treatment
- EFS and OS at 2 years
- Rate of severe (CTCAE grade ≥3) toxicities
- Number of hospitalisation days
- RECORD20-mei-2014 - 11-nov-2017


  • Indien u gegevens wilt toevoegen of veranderen, kunt u een mail sturen naar nederlands@trialregister.nl