This study is a Phase 1b, open-label, single arm dose escalation study of Betalutin followed by rituximab in patients with previously treated follicular lymphoma. The purpose of this study is to characterise the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumour activity of Betalutin in combination with rituximab.

Inclusion Criteria:

• Patient must be ≥18 years at the time of signing the informed consent

• ECOG performance status of 0-2

• Histologically confirmed diagnosis (by 2008 World Health Organization [WHO] classification) of follicular lymphoma (grade 1, 2 or 3a)

• At least one (but not more than 3) prior regimens with an anti-CD20 antibody (alone or in combination with chemotherapy), with documented relapsed, refractory disease (must not be anti-CD20 antibody-refractory) or PD

• Presence of at least one bi-dimensionally measurable lesion by CT or MRI: longest diameter (LDi) >1.5 cm for a nodal lesion; LDi >1.0 cm for an extranodal lesion within 28 days prior to start of treatment

• Normal organ and bone marrow function defined as:

  1. Absolute neutrophil count ≥1.5 x 109/L;
  2. Platelet count ≥150 x 109/L;
  3. Haemoglobin ≥9 g/dL;
  4. Total bilirubin ≤1.5 x upper limit of normal (ULN) (except patients with documented Gilbert's syndrome [<3.0 mg/dL]);
  5. Aspartate transaminase (AST); Alanine transaminase (ALT) or Alkaline phosphatase (ALP) ≤2.5 x ULN (or ≤5.0 x ULN if liver involvement by primary disease);
  6. Adequate renal function as demonstrated by a serum creatinine within the upper limit of normal range

• Bone marrow involvement by lymphoma <25%

• Life expectancy >3 months

• Negative hepatitis B, hepatitis C and human immunodeficiency virus (HIV) screening tests

• Patients must agree to use effective contraception for 12 months following last study drug administration

Exclusion criteria:

• Previous haematopoietic stem cell transplantation (autologous and allogenic)

• Evidence of histological transformation from FL to DLBCL at time of screening.

• Previous total body irradiation

• Chemotherapy, immunotherapy or investigational therapy within 28 days before the start of study drug administration (corticosteroid treatment at doses of ≤20 mg/day, topical or inhaled corticosteroids, granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM CSF] are permitted up to 2 weeks prior to start of study treatment) or failure to recover from AEs associated with prior treatment

• Previous treatment with radioimmunotherapy

• Patients who are receiving any other investigational medicinal products

• Known or suspected central nervous system (CNS) involvement of lymphoma

• History of a previous treated cancer except for the following:

  1. adequately treated local basal cell or squamous cell carcinoma of the skin
  2. cervical carcinoma in situ
  3. superficial bladder cancer or localised prostate cancer undergoing surveillance or surgery
  4. localised breast cancer treated with surgery and radiotherapy but not including systemic chemotherapy
  5. other adequately treated Stage 1 or 2 cancer currently in CR

• Pregnant or lactating women

• Exposure to another CD37 targeting drug

• A known hypersensitivity to RTX, lilotomab, Betalutin or murine proteins or any excipient used in RTX, lilotomab or Betalutin

• Receipt of live, attenuated vaccine within 30 days prior to enrolment

• Evidence of severe or uncontrolled systemic diseases (e.g. ongoing infection, respiratory, cardiac, hepatic or psychiatric conditions) which in the Investigator's opinion would compromise the protocol objectives

All adverse events (AEs) were collected from the time of informed consent until 4 weeks after the last rituximab dose, up to 25 months. Thereafter treatment related AEs were collected up to 36 months for the first two participants only.

Treatment emergent AEs from the first dose of rituximab are presented. Under protocol Versions 1 to 3, it was planned to collect treatment-related AEs for the duration of the follow-up period, up to 5 years. This period was removed under protocol Version 4; only the first two participants had entered the follow-up period at the time this version was approved, therefore only these two participants had treatment-related AEs collected up to 36 months before follow-up was closed.

Whilst the protocol makes reference to a separate statistical analysis plan, given that only seven participants were enrolled and the originally planned expansion phase in a further 20-25 participants was not performed (removed under protocol Version 4.0) a separate detailed statistical analysis plan was not generated.