| 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
Part C: Relapsed indolent Non-Hodgkin B-cell 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"):
Randomised section of Part B:
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.
Selected regimen for further development:
To evaluate the ORR of the regimen selected for further development based on the IRC assessment of tumour response rates in adult patients with relapsed rituximab / anti-CD20 refractory FL.
Part C, phase IIa (Pharmacokinetic Cohort):
To further characterise the pharmacokinetics of Betalutin (total radioactivity measurements in blood) and total lilotomab antibodies (antibodies measured in serum).
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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:
To compare the "40/15" and "100/20" treatment regimens in the randomised section and to evaluate the regimen selected for further development, in terms of the following:
Efficacy
• ORR by investigator assessment
• CRR by independent review and investigator assessment
• DoR by independent review and investigator assessment
• DoCR by independent review and investigator assessment
• PFS by independent review and investigator assessment
• OS.
Safety
• Incidence and severity of adverse events (AEs).
Part C, phase IIa:
• To investigate safety and toxicity.
• To explore efficacy
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A (phase I and phase IIa) and Part C (phase IIa Pharmacokinetic Cohort):
1. Histologically confirmed (by 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.
2. Age ≥ 18 years.
3. Part A: A pre-study WHO performance status of 0-1; Part C: WHO performance status of 0-2.
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 medication 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 (FL 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 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 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.
Please refer to Protocol Section 7.1.2 for all inclusion criteria for Part B (FL phase IIb) |
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| E.4 | Principal exclusion criteria |
Part A (phase I and phase IIa) and Part C (phase IIa Pharmacokinetic Cohort):
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. Part A: Platelet count ≤ 150 x 109 /L; Part C: Platelet count <150x109/L.
For Part C, criteria 2a and 2b must be satisfied within 72 hours of the administration of rituximab.
c. 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).
d. ALP and ALAT ≥ 4x 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).
e. Creatinine ≥ 115 µmol/l (men), 97 µmol/l (women) (Part A only).
Serum creatinine ≥1.5×ULN (Part C only).
f. Haemoglobin <9.0 g/dL (Part C only).
3. Known CNS involvement of lymphoma.
4. Previous total body irradiation.
5. Positive test for HAMA at screening.
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. Part A: Previous treatment with radioimmunotherapy. Part C: Not applicable.
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. Part A and Part C: Test positive for hepatitis B (HBsAg and anti-HBc).
Part C only: Test positive for hepatitis C and HIV.
13. A known hypersensitivity to rituximab, lilotomab, Betalutin or murine proteins or any excipient used in rituximab, lilotomab or Betalutin.
Part B (FL 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 granulocytemacrophage 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). |
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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).
• 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) as assessed by an independent reviewer based on Cheson criteria (version 2014).
Part C:
Pharmacokinetic assessment e.g. total lilotomab antibodies measurements in serum (total lilotomab antibodies pharmacokinetics) and total radioactivity measurements in blood (Betalutin pharmacokinetics). |
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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:
Safety:
• Incidence and severity of AEs
Efficacy:
• ORR by investigator assessment.
• CRR by independent review and investigator assessment.
• DoR by independent review and investigator assessment.
• DoCR by independent review and investigator assessment.
• PFS by independent review and investigator assessment.
• OS.
• Change from baseline in the sum of the product of the greatest perpendicular diameters (SPD) of target lymph nodes as documented radiographically.
Part C:
• Incidence and severity of AEs.
• Tumour response rate.
• Tumour response duration.
• OS. |
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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 | 3 |
| 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 |
| Israel |
| Turkey |
| United States |
| European Union |
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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 | 5 |
| E.8.9.1 | In the Member State concerned months | |
| 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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