Non-Hodgkin B-cell lymphoma Part A: Relapsed indolent Non-Hodgkin B-cell lymphoma Part B: Relapsed follicular lymphoma MedDRA version: 22.0 Level: PT Classification code 10029547 Term: Non-Hodgkin's lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Nordic Nanovector ASA
Eligibility
Sex/Gender
All
Inclusion criteria
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. 1.5 cm for nodal lesion, LDi > 1.0 cm for extra nodal lesion within 28 days prior to start of treatment. 10. 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]). 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 (
Exclusion criteria
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. 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 =2 Graft vs Host Disease (GvHD) in the 8 weeks before date of consent. 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. A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any excipient used in rituximab, lilotomab, or Betalutin. 12. Has received a live-attenua
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part A: Phase I (Arms 1, 2, 3, 4, and 5): To define MTD of Betalutin Phase IIa: To explore tumour response rates in patients receiving Betalutin. Part B (FL phase IIb “PARADIGME”): To evaluate the efficacy of the “40/15” dose regimen (40 mg lilotomab / 15 MBq/kg Betalutin) compared with “100/20” dose regimen (100 mg/m2 lilotomab/ 20 MBq/kg Betalutin) based on an Independent Review Committee (IRC) assessment of tumour response rates in adult patients with relapsed rituximab/anti-CD20-refractory follicular lymphoma. ;Secondary Objective: Part A: Phase I (Arms 1, 2, 3, 4, and 5): To establish recommended dose of Betalutin for phase IIa, investigate safety, toxicity, biodistribution, pharmacokinetics and to explore the efficacy. Phase IIa: to confirm the recommended dose of Betalutin from Part A, phase I, investigate safety and toxicity, estimate progression free survival and overall survival, quality of life. Part B (FL phase IIb “PARADIGME”): To compare the treatment groups in terms of safety (incidence and severity of adverse events (AE)) and efficacy (progression free survival (PFS), overall survival (OS) and duration of response as well as exploratory pharmacokinetics and quality of life measurements (QoL)). ;Primary end point(s): Part A: • Incidence and severity of adverse events and serious adverse events graded according to the National Cancer Institute – Common Terminology Criteria for Adverse Events (CTCAE version 4 or later as applicable). • Changes from baseline in laboratory variables: haematology and serum biochemistry. • Changes from baseline in body temperature and vital signs (systolic/diastolic blood pressure and heart rate) during the treatment period. • Changes from baseline in physical examination during the treatment period. Part B: • Overall response rate (ORR) defined as the proportion of patients who achieve a confirmed CR or PR as assessed by an independent reviewer based on Cheson criteria (version 2014).;Timepoint(s) of e | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part A: • Incidence of potential late toxicity, such as new primary cancers and bone marrow changes (acute myelogenous leukaemia, myelodysplastic syndrome, and aplastic anaemia). • Overall survival. • Estimation of whole-body retention of radioactivity at each imaging time post-injection. • Estimation of the individual organ uptake/retention of radioactivity at each imaging time-point after injection. • Estimate retention of administered radioactivity in blood. • Calculation of estimated absorbed radiation dose to target organs. • Tumour response rate. • Tumour response duration. • Progression-free survival • Performance status defined as improvement or worsening, respectively, by 1-point or more on the ECOG scale from the baseline value • Quality of life (QoL) assessed using Functional Assessment of Cancer Therapy–Lymphoma (FACT-Lym) questionnaire Part B: • Incidence and severity of AEs • DoR – defined as the interval from the first documentation of CR or PR to the first documentation of disease progression or death from any cause, whichever comes first. • PFS – defined as the interval from the start of Betalutin treatment to the first documentation of disease progression. • OS - defined as the interval from the start of Betalutin treatment to death from any cause, including disease progression. • Change from baseline in the sum of the product of the greatest perpendicular diameters (SPD) of target lymph nodes as documented radiographically.;Timepoint(s) of evaluation of this end point: From baseline and up to 5 years post injection | — |
Countries
Australia, Austria, Belgium, Croatia, Czech Republic, Denmark, European Union, Finland, France, Germany, Hungary, Ireland, Israel, Italy, Netherlands, Spain, Sweden, Turkey, United Kingdom, United States
Contacts
Public ContactInformation Desk
Nordic Nanovector ASA
Outcome results
None listed