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    Summary
    EudraCT Number:2011-000033-36
    Sponsor's Protocol Code Number:LYMRIT-37-01
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-10-21
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2011-000033-36
    A.3Full title of the trial
    A phase I/II study of lutetium (177Lu)-lilotomab satetraxetan (Betalutin®) antibody-radionuclide-conjugate for treatment of relapsed non-Hodgkin lymphoma.
    Eine Studie der Phase I/II mit Lutetium (177Lu)-Lilotomab-Satetraxetan (Betalutin®) Antikörper-Radionuklid-Konjugat zur Behandlung von rezidiviertem Non-Hodgkin-Lymphom
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of lymphoma with targeted internal radiation therapy
    (Betalutin)
    A.4.1Sponsor's protocol code numberLYMRIT-37-01
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNordic Nanovector ASA
    B.1.3.4CountryNorway
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportKreftforeningen
    B.4.2CountryNorway
    B.4.1Name of organisation providing supportSkattefunn
    B.4.2CountryNorway
    B.4.1Name of organisation providing supportInnovation Norway
    B.4.2CountryNorway
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNordic Nanovector ASA
    B.5.2Functional name of contact pointInformation Desk
    B.5.3 Address:
    B.5.3.1Street AddressKjelsåsveien 168B
    B.5.3.2Town/ cityOslo
    B.5.3.3Post codeNO-0884
    B.5.3.4CountryNorway
    B.5.4Telephone number+4722183301
    B.5.5Fax number+4722580007
    B.5.6E-mailmail@nordicnanovector.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/03/14/1271
    D.3 Description of the IMP
    D.3.1Product nameBetalutin
    D.3.2Product code Lutetium (177Lu)-lilotomab satetraxetan
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNlutetium (177Lu)-lilotomab satetraxetan
    D.3.9.1CAS number 1453362-90-7
    D.3.9.2Current sponsor code177Lu-DOTA-HH1
    D.3.9.3Other descriptive name177LU-TETRAXETAN-HH1
    D.3.9.4EV Substance CodeSUB121341
    D.3.10 Strength
    D.3.10.1Concentration unit MBq/ml megabecquerel(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number395
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product Yes
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLilotomab
    D.3.2Product code HH1
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLilotomab
    D.3.9.1CAS number 1453362-55-4
    D.3.9.2Current sponsor codeHH1
    D.3.9.3Other descriptive nameTETULOMAB
    D.3.9.4EV Substance CodeSUB121342
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MabThera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1271 in follicular lymphoma
    D.3 Description of the IMP
    D.3.1Product nameMabThera
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MabThera
    D.2.1.1.2Name of the Marketing Authorisation holderRoche
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/14/1271 in follicular lymphoma
    D.3 Description of the IMP
    D.3.1Product nameMabThera
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical 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
    E.1.1.1Medical condition in easily understood language
    Lymph cancer
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.0
    E.1.2Level PT
    E.1.2Classification code 10029547
    E.1.2Term Non-Hodgkin's lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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 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)
    E.2.2Secondary 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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 IIIIA
    (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)
    E.4Principal 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
    <150×109/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 colonystimulating
    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).
    E.5 End points
    E.5.1Primary 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 assessments e.g. total lilotomab antibodies
    measurements in serum (total lilotomab antibodies pharmacokinetics)
    and total radioactivity measurements in blood (Betalutin
    pharmacokinetics).
    E.5.1.1Timepoint(s) of evaluation of this end point
    From baseline until 60 months post injection
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    From baseline and up to 5 years post injection
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    15 MBq/kg Betalutin after 40 mg lilotomab versus 20 MBq/kg Betalutin after 100 mg/m2 lilotumab
    E.8.2.4Number of treatment arms in the trial3
    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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Canada
    Israel
    Korea, Republic of
    Turkey
    United States
    United Kingdom
    European Union
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years13
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years13
    E.8.9.2In all countries concerned by the trial months9
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 66
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 134
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 144
    F.4.2.2In the whole clinical trial 200
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The patient will follow routinely control as requested by treating physician
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-02-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-10-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-10-27
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