Overview

The phase I part (safety assessment of the combination treatment) is aimed at determining the MTD of atezolizumab when combined with BEGEV schedule.

6-18 patients enrolled in this part will be treated with atezolizumab in combination with BEGEV regimen every 3 weeks for 4 cycles.

Patients without a DLT in the first cycle and without disease progression after cycle 2, will undergo stem cell mobilization with 3-4 cycle of A-BEGEV + granulocyte colony-stimulating factor (G-CSF) and subsequently receive a myeloablative therapy followed by ASCT.

The phase IIb part (expansion cohort) plans to randomize 122 patients in two arms (A and B, 61 per arm):

1. arm A will receive the BEGEV regimen followed by ASCT for patients achieving CR.
2. arm B will receive combination treatment with Atezolizumab and BEGEV regimen followed for patients reaching CR by ASCT plus a consolidation with 6 doses of atezolizumab at 1200 mg every 4 weeks.

After the last treatment date of the last patient (LPLT), the phase IIb will be ended. A long term follow up will start, in order to better assess patients' prognosis. All evaluable patients from phase I and phase IIb study will enter in the long term follow up phase and will be followed for 18 months.

Eligibility

Inclusion Criteria:

• 18-60 years old (upper limit valid only for phase I).
• Histologically confirmed cHL, at first disease relapse or refractory to a first-line treatment or with documented persistent disease at interim positron emission tomography (PET) performed after 2 cycles of first line (ABVD/ABVD like/BEACOPP).
• Only one prior systemic therapy for Hodgkin's lymphoma (HL).
• First disease relapse or refractory to a first-line treatment.
• Eligibility for ASCT.
• Performance status (PS) ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) scale.
• Adequate haematological function, unless abnormalities due to underlying disease, at the moment of signing informed consent, defined as follows:
  • neutrophils > or = 1.500/mmc and
  • platelets > or = 75.000/mmc and
  • haemoglobin > or = 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, from 28 days before treatment start up to 3 months after treatment discontinuation, agreeing not to donate semen/eggs during treatment and for 3 months after last treatment dose.

Exclusion Criteria:

• More than one prior systemic therapy for HL.
• 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).
• Previous skin toxicity (i.e. Steven-Johnson Sdr, severe skin reactions.
• Prior allogeneic stem cell transplantation or prior solid organ transplant.
• History of active tubercolosis.
• History of leptomeningeal disease.
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.
• Central nervous system (CNS) involvement by lymphoma.
• Major surgery (excluding any lymph node biopsy) within 28 days prior to signing informed consent.
• Seropositivity for HBV or evidence of active infection. The following categories may be considered for the study:
  • HBsAg positive with HBV DNA < 2000 UI/ml (inactive carriers); HBV DNA > 2000 UI/ml is criteria of exclusion
  • HBsAg negative but HBsAb positive
  • HBsAg negative but HBcAb positive HBsAg positive with HBV DNA < 2000 UI/ml and HBsAg negative but HBcAb positive will be eligible for the study only if they accept to receive antiviral prophylaxis for all the period of treatment and at least for 12 months after the end of therapy. Treatment should be stopped in case of hepatitis reactivation. - Seropositivity for HCV. Patients with presence of HCV antibody are eligible only if PCR result are negative for HCV RNA
• Seropositivity for HIV.
• 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.
• Life expectancy lower than 6 months.
• 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).
• 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.
• 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.
• 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
• Pregnancy or breastfeeding, or unwillingness to comply with adequate contraception (one negative pregnancy test within 14 days prior to initiation of study treatment required).
• 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.

Exception to Exclusion:

• Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
  • Rash must cover < 10% of body surface area
  • Disease is well controlled at baseline and requires only low-potency topical corticosteroids
  • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract

  infection or chronic obstructive pulmonary disease (COPD) exacerbation) are eligible for the study.