Radioimmuntherapie mit Lutetium-(177Lu)-Lilotomab-Satetraxetan (Betalutin®) zur Behandlung von Non-Hodgkin-Lymphom

Drug: 10 MBq/kg Betalutin;Drug: 15 MBq/kg Betalutin;Drug: 20 MBq/kg Betalutin;Drug: 40 mg lilotomab;Drug: 100 mg/m2 lilotomab;Drug: 60 mg/m2 lilotomab;Drug: Rituximab;Drug: 12.5 mBq/kg Betalutin

Gender: All
Maximum age: N/A
Minimum age: 18 Years
Part A and Part C:

Inclusion Criteria:

1. 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.

2. Age = 18 years.

3. Part A: A pre-study WHO performance status of 0-1; Part C: WHO performance status of
0-2.

4. Life expectancy should be =3 months.

5. <25% tumour cells in bone marrow biopsy (biopsy taken from a site not previously
irradiated).

6. Measurable disease by radiological methods.

7. Women of childbearing potential must:

1. understand that the study medication is expected to have teratogenic risk.

2. have a negative pregnancy test.

3. agree to use, and be able to comply with, effective contraception without
interruption, 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.

8. Male patients must agree to use condoms during intercourse throughout study
medication therapy and the following 12 months.

9. Patients previously treated with native rituximab are eligible.

10. The patient is willing and able to comply with the protocol, and agrees to return to
the hospital for follow up visits and examination.

11. The patient has been fully informed about the study and has signed the informed
consent form.

Exclusion Criteria:

Medical contraindications, including uncontrolled infection, severe cardiac, pulmonary,
neurologic, psychiatric or metabolic disease, uncontrolled asthma/allergy requiring
systemic steroids, known to be human immunodeficiency virus (HIV) positive.

2. Laboratory values within 15 days pre-registration:

1. Absolute neutrophil counts (ANC) =1.5?109/L.

2. Part A: Platelet count =150?109/L; Part C: Platelet count <150?109/L. For Part C,
criteria 2a and 2b must be satisfied within 72 hours of the administration of
rituximab

3. Total bilirubin =30 mmol/L (Part A only). Total bilirubin > 1.5?ULN (except patients
with documented Gilbert's syndrome [=3.0 mg/dL]) (Part C only).

4. 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).

5. Creatinine =115 ?mol/L (men), 97 ?mol/L (women) (Part A only). Serum creatinine
=1.5?ULN (Part C only).

6. Haemoglobin <9.0 g/dL (Part C only). 3. Known central nervous system (CNS)
involvement of lymphoma. 4. Previous total body irradiation. 5. Positive test for
human anti-murine antibody (HAMA) at screening. 6. Chemotherapy or immunotherapy
received within the last 4 weeks prior to start of study treatment. Pre treatment
with rituximab is allowed.

7. Pregnant or lactating women. 8. Previous hematopoietic stem cell
transplantation (autologous and allogenic). 9. Part A: Previous treatment with
radioimmunotherapy. Part C: Not applicable. 10. Actively participating in
another study or received an IMP within 4 weeks prior to enrolment.

11. Receipt of live-attenuated vaccine within 30 days prior to enrolment. 12. Part
A and Part C: Test positive for hepatitis B (HBsAg and anti-HBc). Part C only:
Test positive for hepatitis C and human immunodeficiency virus (HIV).

13. A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins
or any excipient used in rituximab, lilotomab, or Betalutin.

Part B:

Inclusion Criteria:

Histologically confirmed (by WHO classification) relapsed non-Hodgkin B-cell FL
(grade I IIIA).

2. Male or female aged =18 years. 3. Received at least 2 prior systemic
anti-neoplastic or immunotherapy-based regimens (maintenance therapy following
a CR/PR is not considered to be a separate line of therapy). Systemic regimens
including agents such as idelalisib or other PI3K inhibitors qualify as a prior
line of therapy.

4. Prior therapy must have included a rituximab/anti-CD20 agent and an alkylating
agent - which may be been administered in separate regimens.

5. Patients must be refractory to any at least one previous regimen that contained
rituximab or an anti CD20 agent, with refractoriness defined as:

i. no response (no CR or PR) during therapy, or ii. 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).

6. 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).

9. Measurable disease by CT or MRI: longest diameter (LDi) >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:

10. 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:

12. Haemoglobin =9.0 g/dL. 13. Total bilirubin =1.5?upper limit of normal (ULN) (except
patients with documented Gilbert's syndrome [<3.0 mg/dL]).

14. Liver enzymes: AST; ALT or ALP =2.5?ULN (or =5.0?ULN with liver involvement by
primary disease).

15. Adequate renal function as demonstrated by a serum creatinine <1.5?ULN. 16. Women of
childbearing potential must:

1. understand that the study medication is expected to have teratogenic risk.

2. have a negative serum beta human-chorionic gonadotropin (?-HCG) pregnancy test at
screening.

3. 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 treatment
administration and for 12 months following administration of Betalutin.

18. The patient is willing and able to comply with the protocol, and agrees to return to
the hospital for follow up visits