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    Summary
    EudraCT Number:2020-005297-10
    Sponsor's Protocol Code Number:DCL-16-001
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-03-22
    Trial 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 ConcernedGreece - EOF
    A.2EudraCT number2020-005297-10
    A.3Full title of the trial
    An Open-Label, Multicenter, Phase 2 Study of CLR 131 in Patients with Relapsed or Refractory (R/R) Select B-Cell Malignancies (CLOVER-1) and Expansion Cohort in Patients with Waldenstrom Macroglobulinemia (CLOVER-WaM)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate the effects of CLR 131 in patients with B-Cell malignancies (CLOVER-1) and expansion study to evaluate the effects of CLR 131 specifically in patients with Waldenstrom Macroglobulinemia (CLOVER-WaM)
    A.4.1Sponsor's protocol code numberDCL-16-001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02952508
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation PlanP/011/2021
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCellectar Biosciences, Inc.
    B.1.3.4CountryUnited States
    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 supportCellectar Biosciences, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCellectar Biosciences, Inc.
    B.5.2Functional name of contact pointClinical Trial Team
    B.5.3 Address:
    B.5.3.1Street AddressCorporate Headquarters, 100 Campus Drive, Suite 207, Florham Park
    B.5.3.2Town/ cityNew Jersey
    B.5.3.3Post code07932
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1608-327-8125
    B.5.5Fax number+1608-216-2162
    B.5.6E-mailclinical@cellectar.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 numberEMA/OD/0000041437
    D.3 Description of the IMP
    D.3.1Product name[131I]-CLR1404 / I-131-CLR1404
    D.3.2Product code CLR 131
    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 INNnot registered INN
    D.3.9.1CAS number 208986-26-9
    D.3.9.2Current sponsor codeCLR 131
    D.3.9.3Other descriptive name18-(p-[131I]-iodophenyl)octadecyl phosphocholine
    D.3.9.4EV Substance CodeSUB193827
    D.3.10 Strength
    D.3.10.1Concentration unit mCi/ml millicurie(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number9 to 11
    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) No
    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.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
    Part A: MM (multiple myeloma), CLL/SLL(chronic lymphocytic leukemia/small lymphocytic lymphoma), LPL/WM(lymphoplasmacytic lymphoma/ Waldenstrom's Macroglobulinemia), MZL(marginal zone lymphoma),MCL(mantle cell lymphoma), DLBCL(diffuse large B-cell lymphoma),and CNSL (central nervous system lymphoma).
    Part B: WM is a B-cell non-Hodgkin lymphoma (NHL), characterized by small B lymphocytes, plasmacytoid lymphocytes, and plasma cells typically involving the bone marrow, lymph nodes, and spleen.
    E.1.1.1Medical condition in easily understood language
    MM is a cancer that forms in plasma cells (a type of white blood cell).CLL/SLL,LPL,MCL,DLBCL and MZL are NHLs that are B-cell in origin.CNSL is a type of NHL involving the central nervous system
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 25.1
    E.1.2Level LLT
    E.1.2Classification code 10054695
    E.1.2Term Waldenstrom's macroglobulinemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10008976
    E.1.2Term Chronic lymphocytic leukemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10076596
    E.1.2Term Marginal zone lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061275
    E.1.2Term Mantle cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10012818
    E.1.2Term Diffuse large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10007953
    E.1.2Term Central nervous system lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10028228
    E.1.2Term Multiple myeloma
    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: The primary objective of the study is to determine the clinical benefit rate (CBR) following the infusion of CLR 131 in patients with R/R select B-cell malignancies, including MM, CLL/SLL, LPL/WM, MZL, MCL, DLBCL, and CNSL, who have had progressive or persistent neoplastic disease despite receiving standard of care for the underlying neoplasm or who are intolerant to the standard of care, based on the response criteria for the respective neoplasm under study.

    Part B: The primary objective of the study is to determine the major response rate (MRR) of CLR 131 in patients with WM who have received at least two prior lines of therapy.
    E.2.2Secondary objectives of the trial
    Part A:
    • To determine the overall response rate (ORR), PFS, time to next treatment (TtNT), overall survival (OS), and duration of response (DOR) in the population under study
    • To further describe the AE profile of CLR 131 in the population under study

    Part B:
    • To determine the overall response rate (ORR), treatment free survival (TFS), duration of response (DOR), and clinical benefit rate (CBR) in the population under study
    • To further describe the safety and tolerability (AE) profile of CLR 131 in the population under study, and in sub-populations
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part A (All patients):
    • Histologically or cytologically confirmed MM; CLL/SLL, LPL/WM, MZL;
    or MCL OR histologically proven, DLBCL. Patients with primary or secondary CNSL may be enrolled.
    • Patient has an Eastern Cooperative Oncology Group (ECOG)
    performance status (PS) of 0 to 2.
    • Patient is 18 years of age or older.
    • Life expectancy of at least 6 months.

    Part A (Multiple myeloma patients)
    • At least quadruple-class refractory disease

    Part B:
    1. Histologically or cytologically confirmed WM. Patients with a diagnosis of LPL may be enrolled with prior Sponsor approval.
    2. Patient has an Eastern Cooperative Oncology Group (ECOG)
    performance status (PS) of 0 to 2.
    3. Patient is 18 years of age or older.
    4. Life expectancy of at least 6 months.
    5. Received at least two prior lines of therapy for WM.
    E.4Principal exclusion criteria
    Part A:
    1. Ongoing Grade 2 or greater toxicities due to previous therapies
    2. Prior external-beam RT resulting in greater than 20% of total bone marrow receiving greater than 20 Gy.
    3. Prior total body or hemi-body irradiation.
    4. Extradural tumor in contact with the spinal cord or tumor located where swelling in response to therapy may impinge upon the spinal cord
    5. Ongoing chronic immunosuppressive therapy
    6. Clinically significant bleeding event, as judged by Investigator, within prior 6 months
    7. Ongoing anti-platelet therapy
    8. Anti-cancer therapy within two weeks of initial CLR 131 infusion
    9. Radiation therapy, chemotherapy, immunotherapy, or investigational therapy within 2 weeks of eligibility-defining bone marrow biopsy
    10. Any other concomitant serious illness or organ system dysfunction that in the opinion of the Investigator would either compromise patient safety or interfere with the evaluation of the safety of the test drug
    11. Active COVID-19 infection with positive test, including patients who are asymptomatic. Patients with prior exposure or infection who are antibody positive, but with no evidence of active COVID-19 disease would be eligible.
    12. For patients with primary or secondary CNSL, active bleeding in the tumor bed and/or uncontrolled seizure activity
    13. Major surgery within 6 weeks of enrollment
    14. History of hypersensitivity to thyroid protection medication
    15. Known history of human immunodeficiency virus, hepatitis C, or hepatitis B infection
    16. Presence of active infection within 72 hours prior to dosing;
    17. Pregnancy or breast-feeding

    Part B:
    1. Ongoing Grade 2 or greater toxicities due to previous therapies, excluding alopecia
    2. Prior external-beam RT resulting in greater than 20% of total bone marrow receiving greater than 20 Gy.
    3. Prior total body or hemi-body irradiation. Patients who have received prior low-dose total body or hemi-body irradiation may be allowed on a case-by-case basis after discussion with Sponsor (considerations may include factors such as time since irradiation, total lifetime accumulated dose, etc.).
    4. Patients with second malignancies in addition to WM, if the second malignancy has required systemic therapy in the last 2 years. Exceptions to this criterion include secondary malignancies in remission, successfully treated skin malignancies, skin malignancies only requiring topic treatment or surgical excision, or other cancer that do not require therapy.
    5. Anti-cancer therapy within two weeks of initial CLR 131 infusion.
    6. Major surgery within 6 weeks of enrollment.
    7. History of hypersensitivity to thyroid protection medication (e.g., potassium iodide, Lugol's solution, etc.).
    8. Known history of human immunodeficiency virus. Active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) defined by positive polymerase chain reaction (PCR). Testing is only required with known or suspected prior history. Hepatitis patients receiving antiviral therapy (e.g., entecavir) who do not have a positive PCR are eligible.
    9. Presence of active infection within 72 hours prior to dosing; patients with ongoing use of prophylactic antibiotics, antifungals, or antivirals are eligible as long as there is no evidence of active infection and the antibiotics, antifungals, or antivirals are not included on the list of prohibited medications.
    10. Pregnancy or breast-feeding.
    E.5 End points
    E.5.1Primary end point(s)
    Part A:
    The primary endpoint is the CBR, which is defined as:
    • the proportion of MM patients following the infusion of CLR 131 with stringent CR (sCR), CR, VGPR, PR, and SD per IMWG criteria;
    • the proportion of lymphomas patients (SLL, MZL, MCL, and DLBCL) following the infusion of CLR 131 with CR, PR, and SD per the Lugano classification CT-based response criteria;
    • the proportion of CLL patients following infusion of CLR 131 with CR, PR, and SD per the iwCLL 2018 Criteria for Response Assessment;
    • the proportion of LPL/WM patients with measurable IgM and/or computed-tomography based response criteria following infusion of CLR
    131 with CR, VGPR, PR, MR, and SD determined from criteria modified from the VIth Waldenstrom's Macroglobulinemia Criteria for Response Assessment.
    • the proportion of CNSL patients following infusion with CLR 131 with
    CR, CRu, PR, and SD per the 2005 Response Criteria for CNS Lymphoma

    Part B:
    The primary endpoint is the MRR, which is defined as the proportion of patients following the infusion of CLR 131 with complete response (CR), very good partial response (VGPR), or partial response (PR) determined from criteria modified from the VIth Waldenstrom's Macroglobulinemia Criteria for Response Assessment up to 12 months post first CLR 131 infusion in WM patients who have received at least two prior lines of therapy.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A:
    MM - Day 22, 29, 36, 43, 57, 64, 85, 106, 127 (then as directed by clinician).

    Part B:
    Day 8, 15, 22, 29, 36, 43, 50, 57
    Month 6 post first CLR 131 infusion year 1 post first CLR 131 infusion
    E.5.2Secondary end point(s)
    Part A:
    The secondary efficacy endpoints include:
    • ORR (overall response rate), PFS (progression free survival), TtNT (time of next treatment), OS (overall survival), DOR (duration of response), DOCB (duration of clinical benefit)

    Overall response rate is defined as:
    • the proportion of MM patients with sCR, CR, very good PR (VGPR), and
    PR per IMWG criteria, or
    • the proportion of lymphoma patients (SLL, MZL, MCL, and DLBCL) with complete (radiologic) response (CR) and PR per the Lugano classification
    CT-based response criteria, or
    • the proportion of CLL patients with CR and PR per the iwCLL 2018
    Criteria for Response Assessment;
    • the proportion of LPL/WM patients with measurable IgM and/or computed-tomographybased response criteria with CR, VGPR, PR, and MR determined from criteria modified from the VIth Waldenstrom's Macroglobulinemia Criteria for Response Assessment.
    • the proportion of CNSL patients following infusion with CLR 131 with
    CR, CRu, and PR per the 2005 Response Criteria for CNS Lymphoma.


    Part B:
    The secondary efficacy endpoints include ORR, TFS, DOR, CBR, and safety. Overall response rate is defined as the proportion of patients with a minor response (MR), PR, VGPR, or CR determined from criteria modified from the VIth Waldenstrom's Macroglobulinemia Criteria for Response Assessment. Treatment free survival is defined as the time from last CLR 131 dose to time to initiation of subsequent therapy or death. Duration of response is defined as the time from the first documentation of response (including CR, VGPR, PR) to progressive disease (PD) or death. Clinical benefit rate is defined as the proportion of patients with CR, VGPR, PR, MR, and SD determined from criteria modified from the VIth Waldenstrom's Macroglobulinemia Criteria for Response Assessment.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part A:
    MM - Day 22, 29, 36, 43, 57, 64, 85, 106, 127 (then as directed by clinician), then every 3 months.

    Part B: Day 1, 8, 15, 22, 29, 36, 43, 50 and 57
    Month 6 post first CLR 131 infusion year 1 post first CLR 131 infusion

    AE/SAE profile is evaluated at all visits
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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) No
    E.7.1.1First administration to humans No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Expansion Cohort
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA19
    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
    Brazil
    Israel
    United States
    Finland
    France
    Spain
    Czechia
    Greece
    Italy
    Portugal
    Turkey
    United Kingdom
    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
    Part A: Patients will be followed until death or patient is lost to follow-up
    Part B: Patients will be assessed for approximately 3 years post initial CLR 131 dosing.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days11
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    A Legally Authorized Representative (LAR) if applicable
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 170
    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)
    None
    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 Decision2021-05-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-15
    P. End of Trial
    P.End of Trial StatusOngoing
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