Study of CLR 131 in Select B-Cell Malignancies (CLOVER-1) and Pivotal Expansion in Waldenstrom Macroglobulinemia

Overview

Part A of this study evaluates CLR 131 in patients with select B-cell malignancies (multiple myeloma( MM), indolent chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) who have been previously treated with standard therapy for their underlying malignancy. Part B (CLOVER-WaM) is a pivotal efficacy study evaluating IV administration of CLR 131 in patients with WM that failed Bruton's tyrosine kinase inhibitors (BTKi).

Full Title of Study: “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)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 2022

Detailed Description

B-cell malignancies represent a diverse collection of diseases and, taken together, make up the majority of hematologic malignancies. B-cell lymphomas represent the largest percentage of these neoplasms, and the relapsed and/or refractory B-cell lymphomas have proven very difficult to treat. Success rate, defined as complete or partial response, is as low as 2% to 4% in many of these diseases, and they remain an area of a significant unmet medical need. Patients that have failed BTKi, including WM patients, represent a very challenging patient population with significantly reduced life-expectancy. CLR 131 is a targeted radiotherapeutic that exploits the selective uptake and retention of Cellectar's proprietary phospholipid ethers (PLEs) by malignant cells. Cellectar Biosciences' novel cancer-targeted small-molecule compound is radiolabeled with the radioisotope iodine-131 (I-131) which has previously been used approved for use in select tumors. CLR 131 has been evaluated in over 80 xenograft and spontaneous (transgenic) tumor models where it was demonstrated to be effective in eliminating tumors. Based on the critical unmet medical need for effective agents with novel mechanisms of action in B-cell malignancies, Cellectar Biosciences has chosen to expand this ongoing study to assess CLR 131 in a pivotal expansion cohort in Waldenstrom's Macroglobulinemia patients that have failed BTKi treatment.

Interventions

  • Drug: CLR 131 single dose
    • Radiopharmaceutical
  • Drug: CLR 131 multiple dose
    • Radiopharmaceutical
  • Drug: CLR 131 fractionated dose
    • Radiopharmaceutical

Arms, Groups and Cohorts

  • Experimental: CLR 131, intravenous administration WM
    • CLR 131 in Waldenstroms Macroglobulinemia
  • Experimental: CLR 131, intravenous administration MM
    • CLR 131 in Multiple Myeloma
  • Experimental: CLR 131 intravenous administration NHL [CLOSED]
    • CLR 131 in Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma, and Diffuse Large B-Cell Lymphoma

Clinical Trial Outcome Measures

Primary Measures

  • Part A [CLOVER-1] Clinical benefit rate
    • Time Frame: 84 days
    • Response assessment per International Uniform Response Criteria for Multiple Myeloma; Lugano Criteria for lymphoma; International Workshop on Chronic Lymphocytic Leukemia for CLL; or VIth Waldenstrom’s Macroglobulinemia Criteria for Response Assessment
  • Part B [CLOVER-WaM] Major Response Rate
    • Time Frame: 12 months
    • Response assessment per criteria modified from VIth Waldenstrom’s Macroglobulinemia Criteria for Response Assessment

Secondary Measures

  • Part A [CLOVER-1] Preliminary efficacy – overall response rate
    • Time Frame: 84 days
    • Response assessment per International Uniform Response Criteria for Multiple Myeloma; Lugano Criteria for lymphoma; International Workshop on Chronic Lymphocytic Leukemia for CLL; or VIth Waldenstrom’s Macroglobulinemia Criteria for Response Assessment
  • Part A [CLOVER-1] time to progression
    • Time Frame: 84 days
    • Response assessment per International Uniform Response Criteria for Multiple Myeloma; Lugano Criteria for lymphoma; International Workshop on Chronic Lymphocytic Leukemia for CLL; or VIth Waldenstrom’s Macroglobulinemia Criteria for Response Assessment
  • Part A [CLOVER-1] overall survival
    • Time Frame: 84 days
    • Response assessment per International Uniform Response Criteria for Multiple Myeloma; Lugano Criteria for lymphoma; International Workshop on Chronic Lymphocytic Leukemia for CLL; or VIth Waldenstrom’s Macroglobulinemia Criteria for Response Assessment
  • Part B [CLOVER-WaM] Overall response rate
    • Time Frame: 12 months
    • Response assessment per criteria modified from VIth Waldenstrom’s Macroglobulinemia Criteria for Response Assessment
  • Part B [CLOVER-WaM] treatment free survival
    • Time Frame: 12 months
    • Response assessment per criteria modified from VIth Waldenstrom’s Macroglobulinemia Criteria for Response Assessment
  • Part B [CLOVER-WaM] duration of response
    • Time Frame: 12 months
    • Response assessment per criteria modified from VIth Waldenstrom’s Macroglobulinemia Criteria for Response Assessment
  • Part B [CLOVER-WaM] clinical benefit rate
    • Time Frame: 12 months
    • Response assessment per criteria modified from VIth Waldenstrom’s Macroglobulinemia Criteria for Response Assessment

Participating in This Clinical Trial

[CLOVER-1] Inclusion Criteria:

All Patients

  • Histologically or cytologically confirmed MM; CLL/SLL, LPL/WM, MZL; or MCL OR histologically proven, DLBCL. Patients with transformed DLBCL are allowed. – ECOG performance status of 0 to 2 – 18 years of age or older – Life expectancy of at least 6 months – Platelets ≥ 75,000/µL (if full-dose anticoagulation therapy is used, platelets ≥ 100,000/µL are required) – WBC count ≥ 3000/µL – Absolute neutrophil count ≥ 1500/µL – Hemoglobin ≥ 9 g/dL (last transfusion, if any, must be at least 1 week prior to study registration, and no transfusions are allowed between registration and dosing) – Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 – Alanine aminotransferase < 3 × upper limit of normal (ULN) – Bilirubin < 1.5 × ULN – International normalized ratio (INR) < 2.5 – If patient is on full-dose anticoagulation therapy, the anticoagulation therapy must be reversible and reversal of the anticoagulation therapy must not be life-threatening, as judged by the Investigator – Patients who have undergone stem cell transplant must be at least 100 days from transplant Patients with Multiple Myeloma – At least 2 prior regimens, which must include at least 1 approved proteasome inhibitor (bortezomib, carfilzomib, or ixazomib) and at least 1 approved immunomodulatory agent (thalidomide, lenalidomide, or pomalidomide), with or without maintenance therapy, unless patients are intolerable to such agents or ineligible to receive such agents. – Progressive disease defined by any of the following: – 25% increase in serum M-protein from the lowest response value during (or after) last therapy and/or absolute increase in serum M-protein of ≥ 0.5 g/dL – 25% increase in urine M-protein from the lowest response value during (or after) last therapy and/or absolute increase in urine M-protein of ≥ 200 mg/24 h – 25% increase in bone marrow plasma cell percentage from the lowest response value during (or after) last therapy. Absolute bone marrow plasma cell percentage must be ≥ 10% unless prior CR when absolute bone marrow plasma cell percentage must be ≥ 5%. – 25% increase in serum FLC level from the lowest response value during (or after) last therapy; the absolute increase must be > 10 mg/dL – New onset hypercalcemia > 11.5 mg/dL – Failure to obtain a partial response or better to current treatment, or cannot further improve their response to current treatment – Appearance of new extramedullary disease – Measurable disease defined by any of the following: – Serum M-protein > 0.5 g/dL – Urine M-protein > 200 mg/24 h – Serum FLC assay: Involved FLC level ≥ 10 mg/dL provided serum FLC ratio is abnormal. – Patients who are non-secretors will be considered for accrual on a case-by-case basis by the Sponsor and will require an Investigator plan to define PD prior to enrollment and to assess clinical benefit after treatment. Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Lymphoplasmacytic Lymphoma/Waldenstom Macroglobulinemia, or Marginal Zone Lymphoma – Prior treatment with at least 2 prior regimens, which may include chemotherapy, an approved anti-CD20 antibody with or without maintenance therapy, and an approved targeted agent, unless patients are ineligible to receive such agents – Patients with Helicobacter pylori+ mucosa-associated lymphoid tissue lymphoma must have received 1 prior antibiotic regimen for H pylori – At least 1 measurable nodal lesion with longest diameter > 15 mm or 1 measurable extranodal lesion (eg, hepatic nodule) with longest diameter > 10 mm. Additional parameters (e.g., measurable IgM for patients with Lymphoplasmacytic Lymphoma) may be allowed if they meet current NCCN guidelines for symptomatic disease. Patients with uptake by FDG-PET scan may be allowed with prior approval of Sponsor. Patients with Mantle Cell Lymphoma – Prior treatment with at least 1 prior regimen – At least 1 measurable nodal lesion with longest diameter > 15 mm or 1 measurable extranodal lesion (eg, hepatic nodule) with longest diameter > 10 mm. Patients with uptake by FDG-PET scan may be allowed with prior approval of Sponsor. Patients with Diffuse Large B-Cell Lymphoma – Relapsed or refractory to combination chemotherapy for DLBCL that contains rituximab and an anthracycline; or is intolerable to such agents. Relapsed disease is defined as either recurrence of disease after a CR or PD after achieving a partial response (PR) or SD. Refractory disease is defined as failure to achieve at least SD with any 1 line of therapy or with PD ≤ 3 months of the most recent chemotherapy regimen. – At least 1 measurable nodal lesion with longest diameter > 15 mm or 1 measurable extranodal lesion (eg, hepatic nodule) with longest diameter > 10 mm. Patients with uptake by FDG-PET scan may be allowed with prior approval of Sponsor. [CLOVER-1] Exclusion Criteria:

  • Ongoing Grade 2 or greater toxicities due to previous therapies. Stable, tolerable Grade 2 AEs (eg, neuropathy) may be allowed. – Prior external-beam RT resulting in greater than 20% of total bone marrow receiving greater than 20 Gy. – 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.) – Extradural tumor in contact with the spinal cord or tumor located where swelling in response to therapy may impinge upon the spinal cord – Central nervous system involvement unless previously treated with surgery or radiotherapy with the patient neurologically stable and off corticosteroids – For patients with CLL/SLL, LPL, or MZL, transformation to a more aggressive form of NHL – Ongoing chronic immunosuppressive therapy – Clinically significant bleeding event within prior 6 months – Ongoing anti-platelet therapy (except low-dose aspirin [eg, 81 mg daily] for cardioprotection) – Anti-cancer therapy within two weeks of initial CLR 131 infusion. Low dose dexamethasone for symptom management is allowed – Radiation therapy, chemotherapy, immunotherapy, or investigational therapy within 2 weeks of eligibility-defining bone marrow biopsy. [CLOVER-WaM] Inclusion Criteria – Histologically or cytologically confirmed WM. Patients with a diagnosis of LPL may be enrolled with prior Sponsor approval. – Patient has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2 (Appendix C) – Patient is 18 years of age or older – Life expectancy of at least 6 months – Received first line standard of care – Failed treatment with a BTK inhibitor or had a sub-optimal response to it. [CLOVER-WaM] Exclusion Criteria – Ongoing Grade 2 or greater toxicities due to previous therapies, excluding alopecia (subject to the additional laboratory abnormalities listed below). However, stable, tolerable Grade 2 AEs (e.g., neuropathy) and gastrointestinal AEs (e.g., nausea) persistent after adequate management may be allowed after discussion with the Medical Monitor. – Prior external-beam RT resulting in greater than 20% of total bone marrow receiving greater than 20 Gy. – 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.) – Patients with second malignancies in addition to WM, if the second malignancy has required therapy in the last 2 years or is not in remission; exceptions to this criterion include successfully treated non-metastatic basal cell or squamous cell skin carcinoma, or prostate cancer that does not require therapy – Anti-cancer therapy within two weeks of initial CLR 131 infusion. – Radiation therapy, chemotherapy, immunotherapy within 2 weeks, and investigational therapy within 5 half-lives of eligibility-defining bone marrow biopsy.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Cellectar Biosciences, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • John Friend, MD, Study Director, Cellectar Biosciences
  • Overall Contact(s)
    • Kate Oliver, 608-327-8125, clinical@cellectar.com

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