A Phase 1/2 Study of Betalutin for Treatment of Relapsed Non-Hodgkin Lymphoma

Part A and Part C:

Inclusion Criteria

• Histologically confirmed (by World Health Organization [WHO] classification) relapsed incurable non-Hodgkin B-cell lymphoma of following subtypes; follicular grade I-IIIA (for Part C, this excludes patients meeting Part B criteria, who should enter Part B), marginal zone, small lymphocytic, lymphoplasmacytic, mantle cell.
• Age ≥ 18 years.
• Part A: A pre-study WHO performance status of 0-1; Part C: WHO performance status of 0-2.
• Life expectancy should be ≥3 months.
• 1.5×ULN (except patients with documented Gilbert's syndrome [≥3.0 mg/dL]) (Part C only).
• Alkaline phosphatase (ALP) and alanine transaminase (ALT) ≥4×normal level (Part A only).

Aspartate transaminase (AST), ALT or ALP >2.5×ULN (or >5.0×ULN with liver involvement by primary disease). (Part C only).

• Creatinine ≥115 µmol/L (men), 97 µmol/L (women) (Part A only). Serum creatinine ≥1.5×ULN (Part C only).
• Haemoglobin 1.5 cm for nodal lesion, LDi >1.0 cm for extra nodal lesion on an assessment performed during the screening period.

Criteria 10 and 11 must be satisfied within 72 hours of the administration of rituximab:

• ANC ≥1.5×109/L. 11. Platelet count ≥100×109/L.

Criteria 12 to 15 must be verified at time of eligibility review within 2 weeks prior to rituximab administration:

• Haemoglobin ≥9.0 g/dL. 13. Total bilirubin ≤1.5×upper limit of normal (ULN) (except patients with documented Gilbert's syndrome [ 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localised prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.

.9. Pregnant or breastfeeding women. 10. Exposure to another CD37 targeting drug. 11. 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. 13. Evidence of severe or uncontrolled systemic diseases:
• Uncontrolled infection including evidence of ongoing systemic bacterial, fungal, or viral infection (excluding viral upper respiratory tract infections) at the time of initiation of study treatment.
• Pulmonary conditions e.g. unstable or uncompensated respiratory disease.
• Hepatic, renal, neurological, or metabolic conditions - which in the opinion of the investigator would compromise the protocol objectives.
• Psychiatric conditions e.g. patients unlikely to comply with the protocol, e.g. mental condition rendering the patient unable to understand the nature, scope, and possible consequences of participating in the study.
• History of erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome.
• Cardiac conditions in the previous 24 weeks (before date of consent), including

i. history of acute coronary syndromes (including unstable angina). ii. class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.

iii. known uncontrolled arrhythmias (except sinus arrhythmia).