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).

1. Male or female aged ≥ 18 years. 3. Received at least 2 prior anti-neoplastic or immunotherapy-based regimens (maintenance therapy following a CR/PR is not considered to be a separate line of therapy).
2. Prior therapy must include rituximab/anti-CD20 agent and an alkylating agent. Prior exposure to other systemic anti-neoplastic agents (including idelalisib or other phosphatidylinositol 3-kinase (PI3K) inhibitors etc.) is also allowed.
3. Patients must be refractory to any previous regimen containing rituximab or an anti-CD20 agent, defined as: no response (no CR/PR) during therapy, or a response (CR/PR) lasting less than 6 months after the completion of a regimen including 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).
4. WHO performance status of 0-2. 7. Life expectancy of ≥ 3 months. 8. Bone marrow tumour infiltration < 25% (in biopsy taken from a site not previously irradiated).
5. Measurable disease by CT or MRI: longest diameter (LDi) > 1.5 cm for nodal lesion, LDi > 1.0 cm for extra nodal lesion within 28 days prior to start of treatment.
6. . ANC ≥ 1.5 x 109/L. 11. Platelet count ≥ 100 x 109/L . 12. Haemoglobin ≥ 9.0 g/dL. 13. Total bilirubin ≤1.5 x upper limit of normal (ULN) (except patients with documented Gilbert's syndrome [< 3.0 mg/dL]).
7. . 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).
8. . Adequate renal function as demonstrated by a serum creatinine < 1.5 x ULN. 16. Women of childbearing potential must:
9. understand that the study medication is expected to have teratogenic risk.
10. have a negative serum beta human-chorionic gonadotropin (ß-HCG) pregnancy test at screening.
11. commit to continued abstinence from heterosexual intercourse (excluding periodic abstinence or the withdrawal method) or begin a highly effective method of birth control with a Pearl-Index < 1%, without interruption, from 4 weeks before starting study medication, throughout study medication therapy and for 12 months after end of study medication therapy, even if she has amenorrhoea. Apart from abstinence, highly effective methods of birth control are: i. Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal).

ii. Progestogen-only hormonal contraception associated with inhibition of ovulation ((oral, injectable, implantable) iii. Intrauterine device (IUD). iv. Intrauterine hormone-releasing system (IUS). v. Bilateral tubal occlusion. vi. Vasectomised partner. 17. Male patients must agree to use condoms during intercourse throughout study medication therapy and the following 12 months.

1. . The patient is willing and able to comply with the protocol, and agrees to return to the hospital for follow-up visits and examination.
2. . The patient has been fully informed about the study and has signed the informed consent form.
3. . Negative HAMA test at screening. 21. Negative Hepatitis B (negative HBsAG and anti-HBC), Hepatitis C and HIV test at screening

Exclusion Criteria:

Prior hematopoietic allogenic stem cell transplantation. Patients with a prior autologous stem cell transplanted (SCT) are excluded unless at least two years have elapsed since transplantation and the patient has been without grade ≥1 Graft vs Host Disease (GvHD) in the 8 weeks before date of consent.

1. Evidence of histological transformation from FL to diffuse large B-cell lymphoma (DLBCL) at time of screening. 4. Previous total body irradiation. 5. 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, 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). Note: excludes pre-treatment with rituximab as part of this study.
2. Patients who are receiving any other investigational medicinal products. 7. Patients with known or suspected CNS involvement of lymphoma. 8. History of a previous treated cancer except for the following:
3. adequately treated local basal cell or squamous cell carcinoma of the skin. b. cervical carcinoma in situ. c. superficial bladder cancer. d. localised prostate cancer undergoing surveillance or surgery. e. localised breast cancer treated with surgery and radiotherapy but not including systemic chemotherapy.
4. other adequately treated Stage 1 or 2 cancer currently in CR. 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.
5. . Has received a live-attenuated vaccine within 30 days prior to enrolment. 13. Evidence of severe or uncontrolled systemic diseases:
6. 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.
7. Pulmonary conditions e.g. unstable or uncompensated respiratory disease.
8. Hepatic, renal, neurological, or metabolic conditions - which in the opinion of the investigator would compromise the protocol objectives.
9. 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.
10. History of erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome.
11. Cardiac conditions in the previous 24 weeks (before date of consent), including
12. 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).