A Phase I/II Study of Betalutin for Treatment of Relapsed Non-Hodgkin Lymphoma

For people ages 18 years and up

Part A:

Inclusion Criteria:

• Histologically confirmed (by WHO classification) relapsed incurable non-Hodgkin B-cell lymphoma of following subtypes; follicular grade I-IIIA, marginal zone, small lymphocytic, lymphoplasmacytic, mantle cell.
• Age ≥ 18 years
• A pre-study WHO performance status of 0-1
• Life expectancy should be ≥ 3 months
• <25% tumour cells in bone marrow biopsy
• Measurable disease by radiological methods

Exclusion Criteria:

• Absolute Neutrophil Counts (ANC) ≤ 1.5 x 109 /l
• Platelet count ≤ 150 x 109 /l
• Total bilirubin ≥ 30 mmol/l
• ALP and ALAT ≥ 4x normal level
• Creatinine ≥ 115 µmol/l (men), 97 µmol/l (women))
• Known CNS involvement of lymphoma
• Previous total body irradiation
• Known history of HAMA
• Chemotherapy or immunotherapy received within the last 4 weeks prior to start of study treatment. Pretreatment with rituximab is allowed
• Previous hematopoietic stem cell transplantation (autologous and allogenic)
• Previous treatment with radioimmunotherapy
• Receipt of live, attenuated vaccine within 30 days prior to enrolment
• Test positive for hepatitis B (HBsAg and anti-HBc)
• A known hypersensitivity to rituximab, HH1, Betalutin or murine proteins or any excipient used in rituximab, HH1 or Betalutin

Part B:

Inclusion Criteria:

• Histologically confirmed (by WHO classification) relapsed non-Hodgkin B-cell FL (follicular grade I-IIIA).
• Male or female aged ≥ 18 years.
• Received at least 2 prior chemotherapy- or immunotherapy-based regimens. Prior therapy must include a rituximab/anti-CD20 agent and alkylating agent. Prior exposure to other systemic anti-neoplastic agents (including idelalisib or other PI3K inhibitors) is also allowed.
• Patients must be refractory to any previous regimen containing rituximab/anti-CD20 agent, defined as no response (no CR or PR) during therapy or a response (CR/PR) lasting less than 6 months after the completion of a regimen of rituximab/anti-CD20 therapy (including occurrence of progressive disease (PD) during rituximab/anti-CD20 maintenance therapy, or within 6 months of completion of maintenance therapy).
• WHO performance status of 0-2.
• Life expectancy of ≥ 3 months.
• Bone marrow tumour infiltration < 25% (in biopsy taken from a site not previously irradiated).
• Measurable disease by CT or MRI: longest diameter (LDi) > 1.5 cm for nodal lesion, LDi > cm for extra nodal lesion within 28 days prior to start of treatment.
• ANC ≥ 1.5 x 109/L.
• Platelet count ≥ 150 x 109/L.
• Haemoglobin ≥ 9.0 g/dL.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except patients with documented Gilbert's syndrome [< 3.0 mg/dL]).
• Liver enzymes: Aspartate transaminase (AST); Alanine transaminase (ALT) or ALP ≤ 2.5 x ULN (or ≤ 5.0 x ULN with liver involvement by primary disease).
• Adequate renal function as demonstrated by a serum creatinine < 1.5 x ULN.
• Negative HAMA test at screening.
• Negative test at screening for Hepatitis B (negative HBsAG and anti-HBC), Hepatitis C and HIV.

Exclusion Criteria:

• Prior hematopoietic allogenic stem cell transplantation.
• Prior autologous stem cell transplantation.
• Evidence of histological transformation from FL to DLBCL at time of screening.
• Previous total body irradiation.
• Prior anti-lymphoma therapy (chemotherapy, immunotherapy or other investigational agent) within 4 weeks prior to start of study treatment (corticosteroid treatment at doses of ≤ 20 mg/day, topical or inhaled corticosteroids, G-CSF or GM-CSF are permitted up to 2 weeks prior to start of study treatment). Note: excludes pre-treatment with rituximab as part of this study.
• Patients with known or suspected CNS involvement of lymphoma.
• History of a previous treated cancer except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, localised prostate cancer undergoing surveillance or surgery, localised breast cancer treated with surgery and radiotherapy but not including systemic chemotherapy, other adequately treated Stage 1 or 2 cancer currently in CR.
• Exposure to another CD37 targeting drug.
• A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any excipient used in rituximab, lilotomab, or Betalutin.
• Has received a live-attenuated vaccine within 30 days prior to enrolment.