E.1 Medical condition or disease under investigation |
E.1.1 | Medical 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. |
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E.1.1.1 | Medical 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. |
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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 | 25.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054695 |
E.1.2 | Term | Waldenstrom's macroglobulinemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008976 |
E.1.2 | Term | Chronic lymphocytic leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10076596 |
E.1.2 | Term | Marginal zone lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061275 |
E.1.2 | Term | Mantle cell lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012818 |
E.1.2 | Term | Diffuse large B-cell lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10007953 |
E.1.2 | Term | Central nervous system lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
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: 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. |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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 systematic 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.
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(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
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(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 |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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) | No |
E.7.1.1 | First administration to humans | No |
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 | No |
E.8.1.1 | Randomised | No |
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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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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 | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
Brazil |
Israel |
United Kingdom |
United States |
Czechia |
Finland |
France |
Greece |
Spain |
Türkiye |
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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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Part A: Patients will be followed until death or patient is lost to followup Part B: Patients will be assessed for approximately 3 years post initial CLR 131 dosing. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 25 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 11 |