Treatment of lymphoma with targeted internal radiation therapy(Betalutin)

Phase 1

• Conditions: on-Hodgkin B-cell lymphomaPart A: Relapsed indolent Non-Hodgkin B-cell lymphomaPart B: Relapsed follicular lymphoma; MedDRA version: 20.0Level: PTClassification code 10029547Term: Non-Hodgkin's lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2011-000033-36-FR
• Lead Sponsor: ordic Nanovector ASA

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2015-06-18
• Last Update Posted: 25 June 2018

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

Part A:
1. 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. For the arm 4, phase 2 expansion cohort patients who are refractory to prior therapy (defined as a lack of response or disease progression within 6 months of completion of therapy) will also be eligible for inclusion.
2. Age = 18 years.
3. A pre-study WHO performance status of 0-1.
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:
a) understand that the study medication is expected to have teratogenic risk.
b) have a negative pregnancy test.
c) agree to use, and be able to comply with, effective contraception without interruption, 4 weeks before starting study drug, throughout study drug therapy and for 12 months after end of study drug therapy, even if she has amenorrhoea.
8. Male subjects must agree to use condoms during intercourse throughout study drug 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.

Part B:
1. Histologically confirmed (by WHO classification) relapsed non-Hodgkin B-cell FL (follicular grade I-IIIA).
2. Male or female aged = 18 years.
3. Received at least 2 prior chemotherapy- or immunotherapy-based regimens.
4. Prior therapy must include rituximab/anti-CD20 agent and an alkylating agent. Prior exposure to idelalisib or other phosphatidylinositol 3-kinase (PI3K) inhibitors is also allowed.
5. Patients must be refractory to the last rituximab/anti-CD20 based treatment, 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 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. A previous regimen is defined as one of the following: at least 2 months of single-agent therapy; at least 2 consecutive cycles of chemotherapy.
7. WHO performance status of 0-2.
8. Life expectancy of = 3 months.
9. Bone marrow tumour infiltration < 25% (in biopsy taken from a site not previously irradiated).
10. Measurable disease by CT: 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.
11. ANC = 1.5 x 109/L.
12. Platelet count = 150 x 109/L .
13. Haemoglobin = 9.0 g/dL.
14. Total bilirubin =1.5 x upper limit of normal (ULN) (except patients with documented Gilbert’s syndrome [< 3.0 mg/dL]).
15. 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).
16. Adequate renal function as demonstrated by a serum creatinine < 1.5 x ULN.
17. 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 an

Exclusion Criteria

Part A:
1. Medical contraindications, including uncontrolled infection, severe cardiac, pulmonary, neurologic, psychiatric or metabolic disease, uncontrolled asthma/allergy requiring systemic steroids, known HIV positive.
2. Laboratory values within 15 days pre-registration:
a. Absolute Neutrophil Counts (ANC) = 1.5 x 109 /l.
b. Platelet count = 150 x 109 /l.
*Patients with a screening platelet count of 100-150 x 109/l may be considered for enrolment in phase II arm 4 following review of safety data by the Safety Review Committee for the patients with a screening platelet count >150 x 109/l treated with 20 MBq/kg Betalutin and 100 mg/m2 lilotomab. The dose of Betalutin administered to patients with a platelet count of 100-150 x 109/l is described in section 6.2.
c. Total bilirubin = 30 mmol/l.
d. ALP and ALAT = 4x normal level.
e. Creatinine = 115 µmol/l (men), 97 µmol/l (women).
3. Known CNS involvement of lymphoma.
4. Previous total body irradiation.
5. Known history of HAMA.
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. Previous treatment with radioimmunotherapy.
10. Actively participating in another study or received an investigational drug within 4 weeks prior to enrolment.
11. Receipt of live, attenuated vaccine within 30 days prior to enrolment.
12. Test positive for hepatitis B (HBsAg and anti-HBc).
13. A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any excipient used in rituximab, lilotomab or Betalutin.

Part B:
1. Prior hematopoietic allogenic stem cell transplantation.
2. Prior autologous stem cell transplantation.
3. 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 granulocytemacrophage 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.
6. 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:
a. 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.
f. other adequately treated Stage 1 or 2 cancer currently in CR.
9. Pregnant or breastfeeding women.
10. Exposure to another CD37 targeting drug.
11. Allergy to X-ray contrast agents.
12. A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any excipient used in rituximab, lilotomab, or Betalutin.
13. Has received a live-attenuated vaccine within 30 days prior to enrolment.
14. Evidence of severe or uncontrolled systemic diseases:
a. Uncontrolled infection including evidence of ongoing

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified