Brentuximab Vedotin Associated With Chemotherapy in Untreated Patients With Hodgkin Lymphoma.

Study Overview
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Brief Summary
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This study aims to evaluate the efficacy of brentuximab vedotin + AVD combination (doxorubicine, vinblastine, dacarbazine) in patients with Hodgkin lymphoma stage I / II with an unfavorable diagnosis, assessed by the negativity of PET (positron emission tomography ) after two cycles of chemotherapy.

Detailed Description
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Patients will receive either ABVD chemotherapy (standard treatment = doxorubicin, bleomycin, vinblastine, dacarbazine) or the Brentuximab vedotin in combination with chemotherapy AVD (study treatment), depending on randomization. Radiotherapy is planned after chemotherapy or immunochemotherapy. PET scans will be performed before inclusion, after 2 cycles of chemotherapy and after 4 cycles of chemotherapy (if PET after two cycles was positive), at the end of treatment and during follow-up period.

Official Title
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Brentuximab Vedotin Associated With Chemotherapy in Untreated Patients With Stage I/II Unfavourable Hodgkin Lymphoma. A Randomized Phase II LYSA-FIL-EORTC Intergroup Study

Conditions
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Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Doxorubicin
* Drug: Bleomycin
* Drug: Vinblastine
* Drug: Dacarbazine
* Drug: Brentuximab Vedotin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed CD30+ classical Hodgkin lymphoma Supradiaphragmatic Ann Arbor clinical stage I or II Previously untreated PET scan without IV contrast at diagnosis available for central review with at least one hypermetabolic lesion Unfavourable (U) characteristics according to the classic EORTC/LYSA clinical prognostic factors, including patients with at least one of the following factors: CSII ≥ 4 nodal areas age ≥ 50 yrs M/T ratio ≥ 0.35 ESR ≥ 50 (without B-symptoms) or ESR ≥ 30 with B-symptoms ECOG performance status 0-2 Life expectancy > 6 months Age 18 to 60 years Availability for periodic blood sampling, study-related assessments, and management of toxicity at the treating institution. Female patients who: Are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile, OR If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, through 6 months after the last dose of study drug, OR agree to completely abstain from heterosexual intercourse Male patients, even if surgically sterilized (ie, status postvasectomy), who: o Agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Written informed consent. Required baseline laboratory data: Absolute neutrophil count ≥ 1,500/µL Platelet count ≥ 75,000/ µL Hemoglobin ≥ 8g/dL Serum total bilirubin ≤ 1.5 X ULN unless the elevation is known to be due to Gilbert syndrome. Serum creatinine ≤ 2.0 mg/dL and/or calculated creatinine clearance > 40 mL/minute (Cockcroft-Gault formula or MDRD) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN Exclusion Criteria: Histological diagnosis different from classical Hodgkin Lymphoma. Nodular lymphocyte predominant subtypes (nodular paragranuloma or Poppema paragranuloma) are excluded. Known cerebral or meningeal disease of any etiology, including signs or symptoms of PML Any sensory or motor peripheral neuropathy ≥ Grade 2 Known history of any of the following cardiovascular conditions Myocardial infarction within 2 years of randomization New York Heart Association (NYHA) Class III or IV heart failure (see Appendix 14) Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities Recent evidence (within 30 days before first dose of study drug) of a left-ventricular ejection fraction <50% Unstable diabetes mellitus (to avoid uninterpretable FDG-PET scan). Known HIV positive HCV positive HBV positive. This means: HBsAg positive HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable viral DNA (HBsAg negative patients and viral DNA negative and patients seropositive due to a history of hepatitis B vaccine are eligible). Any history of cancer during the last 5 years, with the exception of non-melanoma skin tumors. Carcinoma in situ of any type not excluded if complete resection. Dementia or altered mental status Pregnancy or breastfeeding. Previous treatment with any anti-CD30 antibody. Known hypersensitivity to any excipients contained in the BV formulation or known contra-indication to any drug contained in the chemotherapy regimens Treatment with corticosteroids before baseline PET scan Known active viral, bacterial, or fungal infection requiring treatment with antimicrobial therapy or with untreated known active Grade 3 viral, bacterial, or fungal infection, within 2 weeks prior to the first dose of BV Treatment with any investigational drug within 30 days before first cycle of treatment

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ABVD<br>Patients in standard arm receive Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine on Day 1 and D14 of each 4-week-cycle during 4 cycles | Drug: Doxorubicin<br>* 25mg/m2<br>Drug: Bleomycin<br>* 10mg/m2<br>Drug: Vinblastine<br>* 6mg/m2<br>Drug: Dacarbazine<br>* 375mg/m2<br>|
| Experimental: AVD+BV<br>Patients in experimental arm receive Doxorubicin, Vinblastine, Dacarbazine and Brentuximab vedotin on Day 1 and D14 of each 4-week-cycle during 4 cycles | Drug: Doxorubicin<br>* 25mg/m2<br>Drug: Vinblastine<br>* 6mg/m2<br>Drug: Dacarbazine<br>* 375mg/m2<br>Drug: Brentuximab Vedotin<br>* 1.2 mg/kg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PET2 assessment | Assessment of PET after two cycles according to the five-point scale Deauville criteria (Negative = 1, 2, 3 and Positive = 4, 5), based on central review. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete response (CR) rate | according to Cheson 2007 criteria | 16 weeks | 
| Progression free survival (PFS) | Survival without disease progression | 5 years | 
| Overall survival (OS) |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HL