Clinical trial NCT02292979: Brentuximab Vedotin Associated With Chemotherapy in Untreated Patients With Hodgkin Lymphoma.
Official title: Brentuximab Vedotin Associated With Chemotherapy in Untreated Patients With Stage I/II Unfavourable Hodgkin Lymphoma. A Randomized Phase II LYSA-FIL-EORTC Intergroup Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hodgkin Lymphoma
Keywords: HL
Lead sponsor: The Lymphoma Academic Research Organisation
Sponsor class: OTHER
Collaborators: name: Millennium Pharmaceuticals, Inc.
First posted: 2014-11-18
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: PET2 assessment
timeFrame: 8 weeks
Secondary outcomes:
measure: Complete response (CR) rate
timeFrame: 16 weeks
measure: Progression free survival (PFS)
timeFrame: 5 years
measure: Overall survival (OS)
timeFrame: 5 years
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: ZNA Middelheim
city: Antwerpen
country: Belgium
facility: ZNA Stuivenberg
city: Brugge
country: Belgium
facility: A.Z. Sint Jan AV
city: Bruxelles
country: Belgium
facility: Institut Jules Bordet
city: Bruxelles
country: Belgium
facility: UCL Louvain Saint Luc
city: Charleroi
country: Belgium
facility: Grand Hôpital de Charleroi
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Leuven
country: Belgium
facility: U.Z. Leuven - Campus Gasthuisberg
city: Liege
country: Belgium
facility: CHU de Liege
city: Roeselare
country: Belgium
facility: AZ Delta - Campus H. Hartziekenhuis
city: Yvoir
country: Belgium
facility: CHU Dinant Godinne
city: Zagreb
country: Croatia
facility: University Hospital Rebro
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Amiens
country: France
facility: CHU d'Amiens
city: Angers
country: France
facility: CHU d'Angers
city: Annecy
country: France
facility: CH de Annecy
city: Besançon
country: France
facility: CHU Jean Minjoz
city: Bourg en Bresse
country: France
facility: CH de Bourg en Bresse
city: Caen
country: France
facility: Centre François Baclesse
city: Caen
country: France
facility: CHU de Caen
city: Chalon sur Saône
country: France
facility: CH de Chalon sur Saône
city: Chambéry
country: France
facility: CH de Chambéry
city: Clamart
country: France
facility: Hôpital Antoine Béclère
city: Clermont-Ferrand
country: France
facility: CHU de Clermont-Ferrand
city: Corbeil Essonnes
country: France
facility: CH Sud Francilien de Corbeil
city: Créteil
country: France
facility: CHU Henri Mondor
city: Dijon
country: France
facility: CHU de Dijon
city: Grenoble
country: France
facility: CHU de Grenoble
city: La Rochelle
country: France
facility: CH La Rochelle
city: Le Chesnay
country: France
facility: Centre Hospitalier de Versailles - André Mignot
city: Lille
country: France
facility: CHRU de Lille - Hôpital Claude Hurriez
city: Limoges
country: France
facility: CHU de Limoges
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Meaux
country: France
facility: CH de Meaux
city: Metz
country: France
facility: CHR de Metz
city: Montpellier
country: France
facility: CHU de Montpellier - Saint Eloi
city: Mulhouse
country: France
facility: CHU de Mulhouse
city: Nancy
country: France
facility: CHU Nancy Brabois
city: Nantes
country: France
facility: CHU Hôtel Dieu Nantes
city: Nîmes
country: France
facility: CHU de Nîmes
city: Paris
country: France
facility: Hôpital Necker
city: Paris
country: France
facility: Hôpital de la Pitié Salpétrière
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: Hôpital Saint Louis
city: Pessac
country: France
facility: Centre François Magendie
city: Pierre Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Reims
country: France
facility: CHU Robert Debré
city: Rennes
country: France
facility: CHU Pontchaillou
city: Roubaix
country: France
facility: CH de Roubaix
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint Priest en Jarez
country: France
facility: Institut de Cancérologie de Loire
city: Strasbourg
country: France
facility: CHU de Strasbourg
city: Toulouse
country: France
facility: CHU de Toulouse
city: Tours
country: France
facility: CHU Bretonneau
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Amsterdam
country: Netherlands
facility: Academisch Medisch Centrum - Universiteit van Amsterdam
city: Amsterdam
country: Netherlands
facility: Antoni Van Leeuwenhoekziekenhuis
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Delft
country: Netherlands
facility: Reinier De Graaf Gasthuis
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center Nijmegen
city: Rotterdam
country: Netherlands
facility: Erasmus MC Cancer Institute - location Daniel den Hoed
city: Rotterdam
country: Netherlands
facility: Erasmus MC
Study officials:
affiliation: Lymphoma Study Association
name: Marc André, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Lymphoma Study Association
name: Luc Fornecker, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Fornecker LM, Lazarovici J, Aurer I, Casasnovas RO, Gac AC, Bonnet C, Bouabdallah K, Feugier P, Specht L, Molina L, Touati M, Borel C, Stamatoullas A, Nicolas-Virelizier E, Pascal L, Lugtenburg P, Di Renzo N, Vander Borght T, Traverse-Glehen A, Dartigues P, Hutchings M, Versari A, Meignan M, Federico M, Andre M; LYSA-FIL-EORTC Intergroup. Brentuximab Vedotin Plus AVD for First-Line Treatment of Early-Stage Unfavorable Hodgkin Lymphoma (BREACH): A Multicenter, Open-Label, Randomized, Phase II Trial. J Clin Oncol. 2023 Jan 10;41(2):327-335. doi: 10.1200/JCO.21.01281. Epub 2022 Jul 22.