A phase I/II study of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) antibody-radionuclide-conjugate for treatment of relapsed non-Hodgkin lymphoma.

Inclusion Criteria: PART B (phase IIb) , 1. 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 of 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 x 109/L.
11. Platelet count >= 100 x 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 x upper limit of normal (ULN) (except patients with
documented Gilbert*s syndrome [< 3.0 mg/dL]).
14. 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).
15. Adequate renal function as demonstrated by a serum creatinine < 1.5 x ULN.
16. Women of childbearing potential must:
a) understand that the study medication is expected to have teratogenic risk.
b) have a negative serum beta human-chorionic gonadotropin (ß-HCG) pregnancy
test at screening.
c) 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 and examination.
19. The patient has been fully informed about the study and has signed the
informed consent form.
20. Negative HAMA test at screening.
21. Negative test at screening for Hepatitis B (negative HBsAG and anti-HBC),
Hepatitis C and HIV.

Exclusion Criteria: PART B (phase IIb),
1. Prior hematopoietic allogenic stem cell transplantation.
2. Patients with a prior autologous stem cell transplanted (SCT) are excluded
unless at least two years have elapsed since transplantation.
3. Evidence of histological transformation from FL to diffuse large B-cell
lymphoma (DLBCL) at time of screening (transformation to grade IIIB that was
successfully treated with recurrence of grade I-IIIA initial clone is
accepted).
4. Previous total body irradiation.
5. Prior anti-lymphoma therapy (chemotherapy, immunotherapy or other systemic
agent including any 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 rituximab).
6. Patients who are receiving any other investigational medicinal products.
7. Patients with known or suspected CNS involvement of lymphoma.
8. History of malignancy other than FL within 5 years prior to screening,( i.e.
patients with cancer diagnosed within 5 years prior to screening or who were
diagnosed prior to 5 years and were not in CR or were on treatment within 5
years prior to screening), with the exception of malignancies with a negligible
risk of metastasis or death (e.g. 5-year OS rate >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.
12. Has received a live-attenuated vaccine within 30 days prior to enrolment.
13. Evidence of severe or uncontrolled systemic diseases:
a. 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.
b. Pulmonary conditions e.g. unstable or uncompensated respiratory disease.
c. Hepatic, renal, neurological, or metabolic conditions - which in the opinion
of the investigator would compromise the protocol objectives.
d. 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.
e. History of erythema multiforme, toxic epidermal necrolysis, or
Stevens-Johnson
syndrome.
f. 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).