| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Non-Hodgkin B-cell lymphoma
Part A: Relapsed indolent Non-Hodgkin B-cell lymphoma
Part B: Relapsed follicular lymphoma |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029547 |
| E.1.2 | Term | Non-Hodgkin's lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
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| E.2.2 | Secondary objectives of the trial |
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)).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 anti-neoplastic or immunotherapy-based regimens (maintenance therapy following a CR/PR is not considered to be a separate line of therapy).
4. Prior therapy must include rituximab/anti-CD20 agent and an alkylating agent. Prior exposure to other systemic anti-neoplastic agents (including idelalisib or other phosphatidylinositol 3-kinase (PI3K) inhibitors, etc.) is also allowed.
5. Patients must be refractory to any previous regimen containing rituximab or an anti-CD20 agent, defined as:
i. no response (no CR/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 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 (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 medication therapy and the following 12 months.
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 Hepatitis B (negative HBsAG and anti-HBC), Hepatitis C and HIV test at screening |
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| E.4 | Principal 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 ≥1 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-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). |
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| E.5 End points |
| E.5.1 | 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). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline until 60 months post injection |
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| E.5.2 | 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. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From baseline and up to 5 years post injection |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| 15 MBq/kg Betalutin after 40 mg lilotomab versus 20 MBq/kg Betalutin after 100mg/m2 lilotomab |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| European Union |
| Israel |
| Turkey |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 13 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 13 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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