A Phase 1/2 Study of Lutetium (177Lu)-Lilotomab Satetraxetan (Betalutin®) Antibody-radionuclide-conjugate for Treatment of Relapsed Non-Hodgkin Lymphoma.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 191
- 试验地点
- 96
- 主要终点
- Part A, Phase I
研究概览
简要总结
This study is a Phase 1/2 open-label three part study in patients with relapsed indolent Non-Hodgkin's lymohoma (NHL) (Parts A and C) or relapsed/refractory follicular lymphoma (FL) (Part B).
详细描述
Part A of the study was a Phase 1/2a study to assess the safety and preliminary efficacy of different treatment regimens of Betalutin with expansion at the candidate recommended Phase 2 doses. Part B was a dedicated Phase 2b randomized substudy to further assess the efficacy and safety of the candidate recommended Phase II doses. Part C was a Phase 2a fixed dose expansion cohort planned to obtain supplementary pharmacokinetic data.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Age ≥ 18 years.
- •Part A: A pre-study WHO performance status of 0-1; Part C: WHO performance status of 0-
- •Life expectancy should be ≥3 months.
- •<25% tumour cells in bone marrow biopsy (biopsy taken from a site not previously irradiated).
- •Measurable disease by radiological methods.
- •Women of childbearing potential must:
- •understand that the study medication is expected to have teratogenic risk.
- •have a negative pregnancy test.
- •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.
- •Male patients must agree to use condoms during intercourse throughout study medication therapy and the following 12 months.
- •Patients previously treated with native rituximab are eligible.
- •The patient is willing and able to comply with the protocol, and agrees to return to the hospital for follow up visits and examination.
- •The patient has been fully informed about the study and has signed the informed consent form.
排除标准
- •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.
- •Laboratory values within 15 days pre-registration:
- •Absolute neutrophil counts (ANC) ≤1.5×109/L.
- •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
- •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).
- •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).
- •Creatinine ≥115 µmol/L (men), 97 µmol/L (women) (Part A only). Serum creatinine ≥1.5×ULN (Part C only).
- •Haemoglobin <9.0 g/dL (Part C only).
- •Known central nervous system (CNS) involvement of lymphoma.
- •Previous total body irradiation.
- •Positive test for human anti-murine antibody (HAMA) at screening.
- •Chemotherapy or immunotherapy received within the last 4 weeks prior to start of study treatment. Pre treatment with rituximab is allowed.
- •Pregnant or lactating women.
- •Previous hematopoietic stem cell transplantation (autologous and allogenic).
- •Part A: Previous treatment with radioimmunotherapy. Part C: Not applicable.
- •Actively participating in another study or received an IMP within 4 weeks prior to enrolment.
- •Receipt of live-attenuated vaccine within 30 days prior to enrolment.
- •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).
- •A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any excipient used in rituximab, lilotomab, or Betalutin.
- •Inclusion Criteria:
- •Histologically confirmed (by WHO classification) relapsed non-Hodgkin B-cell FL (grade I IIIA).
- •Male or female aged ≥18 years.
- •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.
- •Prior therapy must have included a rituximab/anti-CD20 agent and an alkylating agent - which may be been administered in separate regimens.
- •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).
- •WHO performance status of 0-
- •Life expectancy of ≥3 months.
- •Bone marrow tumour infiltration <25% (in biopsy taken from a site not previously irradiated).
- •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:
- •ANC ≥1.5×109/L.
- •Platelet count ≥100×109/L.
- •Criteria 12 to 15 must be verified at time of eligibility review within 2 weeks prior to rituximab administration:
- •Haemoglobin ≥9.0 g/dL.
- •Total bilirubin ≤1.5×upper limit of normal (ULN) (except patients with documented Gilbert's syndrome [<3.0 mg/dL]).
- •Liver enzymes: AST; ALT or ALP ≤2.5×ULN (or ≤5.0×ULN with liver involvement by primary disease).
- •Adequate renal function as demonstrated by a serum creatinine <1.5×ULN.
- •Women of childbearing potential must:
- •understand that the study medication is expected to have teratogenic risk.
- •have a negative serum beta human-chorionic gonadotropin (ß-HCG) pregnancy test at screening.
- •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.
- •Male patients must agree to use condoms during intercourse throughout study treatment administration and for 12 months following administration of Betalutin.
- •The patient is willing and able to comply with the protocol, and agrees to return to the hospital for follow up visits and examination.
- •The patient has been fully informed about the study and has signed the informed consent form.
- •Negative HAMA test at screening.
- •Negative test at screening for Hepatitis B (negative HBsAg and anti-HBc), Hepatitis C and HIV.
- •Exclusion Criteria
- 另有 21 项未显示
研究组 & 干预措施
Part A, Arm 1: 10 MBq/kg Betalutin with lower dose lilotomab pre-dosing
10 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 40 mg lilotomab (Drug)
Part A, Arm 1: 10 MBq/kg Betalutin with lower dose lilotomab pre-dosing
10 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 10 MBq/kg Betalutin (Drug)
Part A, Arm 1: 15 MBq/kg Betalutin with lower dose lilotomab pre-dosing
15 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 15 MBq/kg Betalutin (Drug)
Part A, Arm 1: 15 MBq/kg Betalutin with lower dose lilotomab pre-dosing
15 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 40 mg lilotomab (Drug)
Part A, Arm 1: 20 MBq/kg Betalutin with lower dose lilotomab pre-dosing
20 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 20 MBq/kg Betalutin (Drug)
Part A, Arm 1: 20 MBq/kg Betalutin with lower dose lilotomab pre-dosing
20 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 40 mg lilotomab (Drug)
Part A, Arm 2: 10 MBq/kg Betalutin with no pre-dosing
10 MBq/kg (based on body weight) Betalutin without pre-dosing
干预措施: 10 MBq/kg Betalutin (Drug)
Part A, Arm 2: 15 MBq/kg Betalutin with no pre-dosing
15 MBq/kg (based on body weight) Betalutin without pre-dosing
干预措施: 15 MBq/kg Betalutin (Drug)
Part A, Arm 3: 15 MBq/kg Betalutin with rituximab pre-dosing
15 MBq/kg (based on body weight) Betalutin with rituximab pre-dosing
干预措施: 15 MBq/kg Betalutin (Drug)
Part A, Arm 3: 15 MBq/kg Betalutin with rituximab pre-dosing
15 MBq/kg (based on body weight) Betalutin with rituximab pre-dosing
干预措施: Rituximab (Drug)
Part A, Arm 4: 15 MBq/kg Betalutin with higher dose lilotomab pre-dosing
15 MBq/kg (based on body weight) Betalutin with 100 mg/m2 (based on body surface area) lilotomab pre-dosing
干预措施: 15 MBq/kg Betalutin (Drug)
Part A, Arm 4: 15 MBq/kg Betalutin with higher dose lilotomab pre-dosing
15 MBq/kg (based on body weight) Betalutin with 100 mg/m2 (based on body surface area) lilotomab pre-dosing
干预措施: 100 mg/m2 lilotomab (Drug)
Part A, Arm 4: 20 MBq/kg Betalutin with higher dose lilotomab pre-dosing
20 MBq/kg (based on body weight) Betalutin with 100 mg/m2 (based on body surface area) lilotomab pre-dosing
干预措施: 20 MBq/kg Betalutin (Drug)
Part A, Arm 4: 20 MBq/kg Betalutin with higher dose lilotomab pre-dosing
20 MBq/kg (based on body weight) Betalutin with 100 mg/m2 (based on body surface area) lilotomab pre-dosing
干预措施: 100 mg/m2 lilotomab (Drug)
Part A, Arm 5: 20 MBq/kg Betalutin with intermediate dose lilotomab pre-dosing
20 MBq/kg (based on body weight) Betalutin with 60 mg/m2 (based on body surface area) lilotomab pre-dosing
干预措施: 20 MBq/kg Betalutin (Drug)
Part A, Arm 5: 20 MBq/kg Betalutin with intermediate dose lilotomab pre-dosing
20 MBq/kg (based on body weight) Betalutin with 60 mg/m2 (based on body surface area) lilotomab pre-dosing
干预措施: 60 mg/m2 lilotomab (Drug)
Part B, Arm 1: 15 MBq/kg Betalutin with lower dose lilotomab pre-dosing
15 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 15 MBq/kg Betalutin (Drug)
Part B, Arm 1: 15 MBq/kg Betalutin with lower dose lilotomab pre-dosing
15 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 40 mg lilotomab (Drug)
Part B, Arm 2: 20 MBq/kg Betalutin with higher dose lilotomab pre-dosing
20 MBq/kg (based on body weight) Betalutin with 100 mg/m2 (based on body surface area) lilotomab pre-dosing
干预措施: 20 MBq/kg Betalutin (Drug)
Part B, Arm 2: 20 MBq/kg Betalutin with higher dose lilotomab pre-dosing
20 MBq/kg (based on body weight) Betalutin with 100 mg/m2 (based on body surface area) lilotomab pre-dosing
干预措施: 100 mg/m2 lilotomab (Drug)
Part B, Arm 3: 12.5 MBq/kg Betalutin with lower dose lilotomab pre-dosing
12.5 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 40 mg lilotomab (Drug)
Part B, Arm 3: 12.5 MBq/kg Betalutin with lower dose lilotomab pre-dosing
12.5 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 12.5 mBq/kg Betalutin (Drug)
Part C: 15 MBq/kg Betalutin with lower dose lilotomab pre-dosing
15 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 15 MBq/kg Betalutin (Drug)
Part C: 15 MBq/kg Betalutin with lower dose lilotomab pre-dosing
15 MBq/kg (based on body weight) Betalutin with 40 mg lilotomab pre-dosing
干预措施: 40 mg lilotomab (Drug)
结局指标
主要结局
Part A, Phase I
时间窗: 12 weeks
Number of participants with dose limiting toxicities (DLTs) in Part A
Part A, Phase IIa
时间窗: 5 years
Tumour response rates in patients in Part A receiving Betalutin based on evaluation of CT scan images including PET/CT imaging (and bone marrow biopsy if applicable).
Part B, Phase IIb
时间窗: up to 5 years
Overall response rate in Part B defined as the number of participants with a best response of complete remission or partial remission at any time
次要结局
未报告次要终点