Phase I-II Study in CD30 Positive Diffuse Large B-cell Lymphoma Patients Refractory to First Line Chemotherapy or in First Relapse

Inclusion Criteria:

• CD30 positive DLBCL, i.e. more than 1% of DLBCL cells CD30 positive(central pathologyreview results not required to enter patient into the study), according to the WHOclassification 2008:
• CD30 positive DLBCL, including EBV positive DLBCL
• CD30 positive primary mediastinal B-cell lymphoma
• Primary refractory to or in first relapse after first line therapy with R-CHOP orR-CHOP-like therapy
• Relapse is defined as biopsy confirmed CD30 positive DLBCL after a completeresponse. The relapse must be histologically confirmed. In case a surgical biopsyis not possible, at least confirmation by FNA biopsy is required
• Refractory disease is defined as:

1. progressive disease during first line therapy, In this case biopsyconfirmation of CD30 positive DLBCL is preferred but not required
2. stable disease after at least 3 cycles of first line therapy, In this casebiopsy confirmation of CD30 positive DLBCL is preferred but not required
3. PR after at least 6 cycles of first line therapy, or in the case of stageI-II disease after at least 3 cycles of therapy and definitive involvedfield radiotherapy. In this case refractory disease must be histologicallyconfirmed

• Age ≥ 18 years (upper age limit for ASCT at the discretion of the participatingcenter)
• Measurable disease: on CT scan at least 1 lesion/node with a long axis of > 1.5 cm andat least one positive lesion on 18F-FDG PET scan
• WHO performance status 0-2, status 3 only if disease related (see appendix C)
• Adequate hepatic function: total bilirubin ≤ 1.5 times ULN (unless due to lymphomainvolvement of the liver or a known history of Gilbert's syndrome as defined by > 80%unconjugated bilirubin) and ALAT/ASAT ≤ 3 times ULN (unless due to lymphomainvolvement of the liver; in that case ALAT/ASAT may be elevated up to 5 times ULN)
• Adequate renal function: GFR > 60 ml/min as estimated by the Cockroft&Gault formula atrehydration: CrCL = (140-age [in years] x weight [kg] (x 0.85 for females) / (0.815 xserum creatinine [μmol/L])
• Adequate bone marrow function: Absolute neutrophil count (ANC) ≥ 1.5x109/L andplatelet count ≥ 100 x 109/L, unless caused by diffuse bone marrow infiltration by theNHL
• Hemoglobin must be ≥ 8 g/dL (5.0 mmol/L), transfusion is allowed
• Eligible for high-dose chemotherapy and ASCT
• Resolution of relevant toxicities from first-line therapy
• Life expectancy of > 3 months with treatment
• Negative pregnancy test at study entry, if applicable
• Female patient is either post-menopausal for at least 1 year before screening visit orsurgically sterile or if of childbearing potential, agrees to practice 2 effectivemethods of contraception, at the same time, or agrees to completely abstain fromheterosexual intercourse, from the time of signing the informed consent through 12months after the last dose of study drug
• Male patients, even if surgically sterilized, (i.e. status post vasectomy) agree topractice effective barrier contraception, or agrees to completely abstain fromheterosexual intercourse, during the entire study period and through 12 months afterthe last dose of study drug
• Written informed consent
• Patient is capable of giving informed consent

Exclusion Criteria:

• Peripheral sensory or motor neuropathy grade ≥ 2
• Known cerebral or meningeal disease (NHL or any other etiology), including signs andsymptoms of progressive multifocal leukoencephalopathy (PML)
• Symptomatic neurological disease compromising normal activities of daily living orrequiring medications
• Transformed lymphoma
• DLBCL after organ transplantation
• Immunodeficiency-associated B-cell lymphoproliferative disease
• Use of other investigational agents within at least 5 half-lives of the most recentagent used prior to study entry
• Treatment with myelosuppressive chemotherapy or biological therapy ≤ 4 weeks beforestudy entry
• Female patients who are breast feeding
• History of another malignancy less than 3 years before study inclusion, or previouslydiagnosed with another malignancy and have evidence of residual disease, with theexception of non-melanoma skin cancer, completely resected melanoma TNMpT1 andcarcinoma in situ of the uterine cervix
• Known hypersensitivity to recombinant proteins, murine proteins, or to any excipientcontained in the drug formulation of brentuximab vedotin
• Active hepatitis B or C infection as defined by positive serology and transaminitis.Non-active hepatitis B carriers or anti-HBc positive patients may be included ifprotected with lamuvidine or entecavir (see 9.4)
• HIV positivity
• Radiation therapy within 8 weeks prior to start of protocol treatment. Emergencyradiation therapy is allowed, as long as measurable disease (at non-irradiated sites)persists
• Patients with a serious psychiatric disorder that could, in the investigator'sopinion, potentially interfere with the completion of treatment according to protocol
• Major organ dysfunction, unless NHL-related
• Patients who have any severe and/or uncontrolled medical condition or other conditionsthat could affect their participation in the study such as:
• Known history of symptomatic congestive heart failure (NYHA III, IV, appendix E),myocardial infarction ≤ 6 months prior to first study drug
• Evidence of current serious uncontrolled cardiac arrhythmia, angina pectoris,electrocardiographic evidence of acute ischemia or active conduction systemabnormalities
• Recent evidence (within 6 months before first dose of study drug) of aleft-ventricular ejection fraction <45%
• Severely impaired pulmonary function as defined as spirometry and DLCO (diffusingcapacity of the lung for carbon monoxide) that is 50% or less of the normalpredicted value and/or O2 saturation that is 90% or less at rest on room air
• Thyroid abnormalities when thyroid function cannot be maintained in the normal rangeby medication
• Current participation in another clinical trial interfering with this trial
• Any psychological, familial, sociological and geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule
• Claustrophobia to the extent that PET-CT is impossible