An Open-Label, Multicenter, Phase 2 Study of Iopofosine I 131 (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)

Description

Part A of this study evaluates iopofosine I 131 (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), diffuse large B-cell lymphoma (DLBCL), and central nervous system lymphoma (CNSL) 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 iopofosine I 131 in patients with WM that have received at least two prior lines of therapy.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. Patients that have failed prior th

Trial Eligibility

\[CLOVER-1\] Inclusion Criteria: All Patients * Histologically or cytologically confirmed MM; Patients with primary or secondary CNSL may be enrolled. * 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 * Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 × 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 5 prior regimens, which must include at least 1 approved proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), at least 1 approved immunomodulatory agent (thalidomide, lenalidomide, or pomalidomide), and at least 1 approved monoclonal antibody (e.g., daratumumab or elotuzumab) with or without maintenance therapy, unless patients are intolerable to such agents or ineligible to receive such agents. * At least triple-class refractory (refractory to a proteasome inhibitor, immunomodulatory agent, and a monoclonal antibody) * 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. \[CLOSED\] 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. \[CLOSED\] 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. \[CLOSED\] 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. Patients with CNS Lymphoma * Must have biopsy-proven disease and must have received at least one prior intervention for their disease. * Must be at least two weeks from CNS biopsy before administration of iopofosine I 131. * Must have at least one lesion with enhancement on brain imaging. * Stable (or decreasing) dose of corticosteroids or anti-convulsant medication for at least 7 days prior to dosing \[CLOVER-1\] 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 * 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 iopofosine I 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. * For patients with primary or secondary CNSL, active bleeding in the tumor bed and/or uncontrolled seizure activity \[CLOVER-WaM\] 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 at least two prior lines of therapy for WM * Measurable IgM (above upper limit of normal) OR at least one measurable nodal lesion with longest diameter \> 15 mm or one measurable extranodal lesion (e.g., hepatic nodule) with longest diameter \> 10 mm \[CLOVER-WaM\] Exclusion Criteria * Ongoing Grade 2 or greater toxicities due to previous therapies, excluding alopecia. * 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 iopofosine I 131 infusion. * Need for acute treatment of WM (e.g., those with hyperviscosity)

Study Info

Interventions

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