Study Comparing ABVD vs BEACOPP in Advanced Hodgkin's Lymphoma

Study Overview
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Brief Summary
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The choice of a preferred first-line treatment requires balancing the desire for optimal disease control with the occurrence of early and late treatment-related effects. To fully assess this balance, the treatment decision process should ideally take into account the outcome following a consistent second-line therapy, in particular when tolerated, widely applicable and highly effective salvage regimens exist, like in Hodgkin lymphoma failing initial chemotherapy.

Detailed Description
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During the last two decades ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) has been considered as the standard of care for advanced HL, however 20-30% of the patients fail to achieve a durable complete remission and need a salvage treatment. After a state-of-the art-salvage program including high-dose chemotherapy and autologous hematopoietic stem cell support (ASCT) at least half of these patients achieve a durable disease control. Recently the German Hodgkin Study Group (GHSG) has developed a new regimen, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone), administered with or without dose escalation. In an interim analysis after 23 months follow-up, BEACOPP demonstrated a higher activity compared to COPP/ABVD with a superior freedom from treatment failure (84% versus 75%, P=.034). Despite the improved efficacy a substantial proportion of patients receiving escalated BEACOPP experienced severe acute hematologic toxicity (grade 3-4 leucopoenia, thrombocytopenia and anemia occurred in 78% , 36% and 27% of the cycles administered, respectively) and 1.8% fatal acute toxicities were reported. Moreover of greater concern is the incidence of almost fatal secondary acute leukemia and myelodysplastic syndrome (3 cases in 323 patients). The choice of first-line treatment requires balancing the desire for optimal disease control with the occurrence of early and late treatment-related toxicities. Long-term outcome following an optimal salvage treatment, consisting in high-dose chemotherapy with ASCT should also be taken into consideration. In the present study we plan to compare the efficacy and toxicity of two therapeutic strategies consisting in two different first-line treatments followed by a pre-planned salvage program, when indicated

Official Title
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Prospective Randomized Comparison of ABVD Versus BEACOPP Chemotherapy With or Without Radiotherapy for Advanced Stage or Unfavorable Hodgkin's Lymphoma (HL)

Conditions
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Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Bleomycin
* Drug: Etoposide
* Drug: Doxorubicin
* Drug: Cyclophosphamide
* Drug: Vincristine
* Drug: Procarbazine
* Drug: Prednisone
* Drug: Doxorubicin
* Drug: Bleomycin
* Drug: Vinblastine
* Drug: Dacarbazine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, newly diagnosed Hodgkin's lymphoma (pathological review diagnosis available) No prior treatment Stage II B, III A and B, IV A and B Normal hematopoietic function as measured by leucocytes equal to or greater than 3500/mm3, neutrophils equal to or greater than 1500/mm3, platelets equal to or greater than 100000/mm3 Normal renal function (serum creatinine < 1,5x ULN) and normal liver function (SGOT/SGPT equal to or lower than 2.5x ULN; bilirubin equal to or lower than 1.5x ULN) No significant history or current evidence of cardiovascular disease, or major respiratory disease No severe neurologic or psychiatric disease No other malignancy except basal cell carcinoma of the skin and/or in situ cervical carcinoma of the uterus Serological negativity for hepatitis B or C or HIV infection ECOG performance status equal to or lower than 2 Life expectancy of at least three months Effective contraception in all patients and a negative pregnancy test for women of childbearing potential Written informed consent and consent to a regular follow-up in the outpatient clinic Exclusion criteria: Sever central nervous system or psychiatric disease History or current evidence of clinically significant cardiac disease (congestive heart failure, uncontrolled hypertension, unstable coronary artery disease or myocardial infarction or severe arrhythmias. Left ventricular ejection fraction < 50% at rest by echocardiography or < 55% by isotopic measurement Serological positivity for HBV, HCV or HIV History or current evidence of malignancy other than basal cell carcinoma of the skin, carcinoma in situ of the cervix Lactating or pregnant women

Ages Eligible for Study
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Minimum Age: 17 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm B<br>BEACOPP (Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) for 4 escalated cycles followed by 4 standard cycles | Drug: Bleomycin<br>* 10 mg/m2 IV day 8 during cycles 1 to 8<br>* Other names: Bleomicina Teva;Drug: Etoposide<br>* 200 mg/m2 iv on days 1 to 3 during cycles 1 to 4; 100 mg/m2 iv on days 1 to 3 during cycles 5 to 8<br>* Other names: VP-16, Etoposide Teva;Drug: Doxorubicin<br>* 35 mg/2 iv on day 1 during cycles 1 to 4; 25 mg/m2 iv on day 1 during cycles 5 to 8<br>* Other names: Adriblastina Pfizer;Drug: Cyclophosphamide<br>* 1250 mg/m2 iv on day 1 during cycles 1 to 4; 650 mg/m2 iv on day 1 during cycles 5 to 8<br>* Other names: Endoxan Baxter;Drug: Vincristine<br>* 1.4 mg/m2 iv (max 2 mg) on day 8 during cycles 1 to 8<br>* Other names: Vincristina Teva Italia;Drug: Procarbazine<br>* 100 mg/m2 po from day 1 to 7 during cycles 1 to 8<br>* Other names: Natulan;Drug: Prednisone<br>* 40 mg/m2 po from day 1 to 14 during cycles 1 to 8<br>* Other names: Deltacortene;|
| Active Comparator: Arm A<br>ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for 6 to 8 cycles | Drug: Doxorubicin<br>* 25 mg/m2 iv on days 1 and 15 in each cycle<br>* Other names: Adriblastina Pfizer;Drug: Bleomycin<br>* 10 mg/m2 iv on days 1 and 15 in each cycle<br>* Other names: Bleomicina Teva;Drug: Vinblastine<br>* 6 mg/m2 iv on days 1 and 15 in each cycle<br>* Other names: Velbe;Drug: Dacarbazine<br>* 375 mg/m2 iv on days 1 and 15 in each cycle<br>* Other names: Dacarbazina Medac;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom from first progression at 5 years |  | After a median of 5 years from start of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Freedom from second progression at 5 years |  | After a median of 5 years from start of protocol | 
| Overall survival at 5 years |  | After a median of 5 years from start of the protocol | 
| Number of participants with acute adverse events at initial therapy and at salvage therapy as a measure of safety and tolerability |  | After 3 months from last intervention | 
| Number of participants long term sequelae | Number of participants who developed leukemia Number of participants who developed solid tumors Number of participants who developed cardiovascular disease | After a median of 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hodgkin lymphoma, ABVD, BEACOPP, Salvage high dose chemotherapy