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

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

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.

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.

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