Study of Safety and Efficacy of Betalutin and Rituximab in Patients With FL

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1b Open-label Study of Betalutin in Combination With Rituximab in Patients With Relapsed/Refractory Follicular Lymphoma (Archer-1)

Conditions
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Non Hodgkin Lymphoma, Follicular Lymphoma, Relapsed Follicular Lymphoma

Intervention / Treatment
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* Drug: 10 MBq/kg Betalutin
* Drug: 15 MBq/kg Betalutin


Participation Criteria
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Eligibility Criteria
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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: Absolute neutrophil count ≥1.5 x 109/L; Platelet count ≥150 x 109/L; Haemoglobin ≥9 g/dL; Total bilirubin ≤1.5 x upper limit of normal (ULN) (except patients with documented Gilbert's syndrome [<3.0 mg/dL]); 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); 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: adequately treated local basal cell or squamous cell carcinoma of the skin cervical carcinoma in situ superficial bladder cancer or 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 MBq/kg Betalutin with rituximab treatment<br>10 MBq/kg Betalutin administered with lilotomab pre-dose on day 0; rituximab administered weekly x 4 doses from day 7, then every 3 months for 2 years | Drug: 10 MBq/kg Betalutin<br>* 10 MBq/kg Betalutin, lilotomab 40mg, rituximab 375 mg/m2<br>|
| Experimental: 15 MBq/kg Betalutin with rituximab treatment<br>15 MBq/kg Betalutin administered with lilotomab pre-dose on day 0; rituximab administered weekly x 4 doses from day 7, then every 3 months for 2 years | Drug: 15 MBq/kg Betalutin<br>* 15 MBq/kg Betalutin, lilotomab 40mg, rituximab 375 mg/m2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability: Frequency and Severity of Adverse Events (CTCAE v4.03) | Safety and tolerability of Betalutin in combination with rituximab as determined by the frequency and severity of adverse events (CTCAE v4.03) in the first 12 weeks after Betalutin | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary Anti-tumour Activity | Best overall response of combination treatment using tumour responses based on CT and PET/CT imaging (classified as as complete response, partial response, no response/stable disease or progressive disease as described in Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification) | 25 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radioimmunotherapy, Lu-177, Betalutin, Phase 1b, Combination, Rituximab