phase I/II b study of atezolizumab and BEGEV as first salvage treatment in patients with relapsed or refractory Hodgkin’s lymphoma candidate to autologous stem–cell transplantation

Prior treatment

• More than one prior systemic therapy for HL.
• Seropositivity for HBV or evidence of active infection. The following categories may be considered for the study: • HBsAg positive with undetectable HBV DNA (inactive carriers). • HBsAg negative HBsAb positive and HBcAb negative (vaccinated patients) • HBsAg negative but HBcAb positive from previous infection, providing that they are given antiviral prophylaxis.
• Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail bed) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics except if for tumor fever) within 2 weeks of the start of Cycle 1.
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.
• Pregnancy or breastfeeding, or unwillingness to comply with adequate contraception (one negative pregnancy test within 14 days prior to initiation of study treatment required).
• Previous skin toxicity (i.e. Steven-Johnson Sdr, severe skin reactions.
• Prior allogeneic stem cell transplantation or prior solid organ transplant.
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.
• Major surgery (excluding any lymph node biopsy) within 28 days prior to signing informed consent.

Other illness

• Seropositivity for HCV. Patients with presence of HCV antibody are eligible only if PCR result are negative for HCV RNA
• Seropositivity for HIV.
• Prior history of malignancies, other than HL, unless the patient has been free for at least 5 years (exceptions: localized non-melanoma skin cancer ad carcinoma in situ of the cervix).
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• Presence of autoimmune disease (based on medical history): systemic lupus erythematosus, autoimmune thyroid disease (Hashimoto’s thyroiditis, Basedow’s disease), Sjögren’s syndrome, glomerulonephritis, multiple sclerosis, rheumatoid arthritis, vasculitis, idiopathic pulmonary fibrosis (includine bronchiolitis obliterans organizing pneumonia) and inflammatory bowel disease (Crohn’s disease, ulcerative colitis).
• History of active tubercolosis.
• History of leptomeningeal disease.

Lab values

• Any of the following laboratory abnormalities: liver enzymes (AST/SGOT and/or ALT/SGPT) > 3 fold the upper limit of normal (except of liver involvement by lymphoma); total bilirubin > 1.5 mg/dL (except for patients with known Gilbert’s disease or biliary tree compression by lymphoma masses); creatinine clearance < 30 mL/min.
• Any serious medical condition, laboratory abnormality or psychiatric illness that would prevent the patient from signing the informed consent or which may place the patient at unacceptable risk if participating in the study.

Other

• Life expectancy lower than 6 months.
• Central nervous system (CNS) involvement by lymphoma.

• 18-60 years old (upper limit valid only for phase I).
• Histologically confirmed cHL: 1) at first disease relapse or refractory to a first-line treatment including: - ABVD/ABVD like regimen - BEACOPP/BEACOPP like regimen - BV-AVD regimen - ABVD/ABVD like (2 cycles) intensified with BEACOPP/BEACOPP like regimen due to persistence of disease at interim positron emission tomography (PET). 2) with documented persistent disease at interim PET (DS4-5) performed after 2 cycles of ABVD/ABVD like regimen.
• Only one prior systemic therapy for Hodgkin’s lymphoma (HL).
• Eligibility for ASCT.
• Performance status (PS) ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) scale.
• Adequate haematological function, unless due to bone marrow involvement by lymphoma, at the moment of signing informed consent, defined as follows: • neutrophils >= 1.500/mmc and • platelets >=75.000/mmc and • haemoglobin >= 8,0 g/dL with transfusion independence
• Capacity and willingness to adhere to study visit schedule and specific protocol procedures.
• Compliance with effective contraception without interruption, according to physician’s judgement, from 28 days before treatment start up to at least 6 months after treatment discontinuation, agreeing not to donate semen/eggs during treatment and for at least 6 months after last treatment dose.