Longcor, Jarrod

Background/Objectives: Patients with relapsed/refractory multiple myeloma (RRMM) have poor survival outcomes and limited treatment options. The increasing utilization of multiagent therapies for earlier lines of treatment and novel drug classes including BCMA-targeting agents in subsequent lines of therapy has created a need for innovative treatment platforms in patients who have relapsed after or are refractory to these current standard-of-care approaches. Iopofosine I 131 is a 131iodide (131I)–phospholipid conjugate that exploits the selective uptake and retention of phospholipid ethers through lipid rafts to facilitate tumor delivery of 131I. Methods: The objective of this phase 1 dose-escalation study was to assess the safety and tolerability of single and fractionated dose schedules of iopofosine I 131 + low-dose dexamethasone in heavily pretreated patients with RRMM. Results: The most common AEs overall were cytopenias, notably thrombocytopenia (93.5%), lymphopenia (74.2%), anemia (71%), leukopenia (61.3%), and neutropenia (58.1%). All patients experiencing hematologic adverse events recovered from those events with median time of recovery 21 days post-nadir. Nonhematologic adverse events were mostly limited to Grade 1 and 2. Dose-limiting toxicities included four Grade 4 thrombocytopenia events lasting longer than 7 days, one Grade 4 neutropenia, and one Grade 3 insomnia. The DMC determined 31.25 mCi/m2 was the maximum tolerated dose in the single-dose group, and 20 mCi/m2 × 2 doses was the maximum tolerated dose in the fractionated-dose group. For patients monitored through 85 days following the first infusion, 22 of 26 (84.6%) achieved stable disease after treatment, and 4 of 26 (15.4%) achieved a partial response. Conclusions: A favorable safety and tolerability profile and preliminary clinical activity support further development of iopofosine I 131 in RRMM.

7094 Background: Waldenström Macroglobulinemia (WM) remains incurable with current available therapeutic options. Treatment options for relapsed/refractory pts are limited and often continuous, underscoring the need for new agents with novel mechanisms of action and pt-centered, fixed duration therapy. Iopofosine I 131 is a novel radiopharmaceutical compound composed of a lipid raft-targeting phospholipid ether covalently bound to 131 I, a beta emitting radioisotope. Here, we report preliminary sub-group results of the CLOVER-WaM study [NCT02952508] in WM pts treated with a Bruton’s Tyrosine Kinase inhibitor (BTKi) immediately prior to iopofosine. Methods: Eligible WM pts had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m 2 on days 1 and 15 of each 57-day cycle. The primary efficacy endpoint was major response rate (MRR; partial response or better, as determined by the modified IWWM-VI). Secondary and exploratory endpoints included overall response rate (ORR), treatment-free survival (TFS), progression free survival (PFS), duration of response (DOR), and clinical benefit rate (CBR; stable disease or better). Herein, efficacy endpoints were assessed in the modified intent-to-treat (mITT) population (all pts who received ≥60 mCi total administered dose of iopofosine I 131), and whose treatment regimen prior to iopofosine included a BTKi. Safety was evaluated using CTCAE v4.03 in pts who received ≥1 dose of iopofosine. Data cut off for this analysis was Jan. 16, 2026. Results: As previously reported, 65 pts were dosed and 55 are included in the mITT population. Of those, 22 (40%) had received a BTKi containing regimen immediately prior to iopofosine; and 11 who previously received at least 2 regimens utilizing BTKis and 12 who were refractory to rituximab. In this subgroup, median age was 70.5 (range 55-88), 17 (77%) were male, and 5 (23%) were female. The median number of prior therapies was 3 (range 2-7), 15/22 (68%) were MYD88 mutated and 18/22 (82%) were TP53 wildtype. The MRR was 15/22 (68.2%), ORR was 19/22 (86.4%) and CBR was 100%, median PFS was 12 months (range 1.6 to 28.0) and median TFS was 19.1 months (range 2.5-34.4). Grade ≥ 3, related treatment emergent adverse events (TEAE) occurring in > 10% of pts included anemia (41%), leukopenia (41%), neutropenia (58%), and thrombocytopenia (86%). Conclusions: Iopofosine I 131 demonstrated significant efficacy; 100% CBR, 86.4% ORR and 68.2% MRR with a median PFS of 12 months (range: 1.6 – 28.0 months) in a pt population with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile with cytopenias as the only Grade 3 or greater TEAE. Based on the results of this pivotal trial, iopofosine I 131 could be a promising novel treatment for WM pts after BTKi therapy. Clinical trial information: NCT02952508 .

Introduction: Waldenström macroglobulinemia (WM)remains incurable with current therapies. Treatment options for patients beyond initial therapy are limited, underscoring the need for new agents with novel mechanisms of action. Iopofosine I 131 is a novel radiopharmaceutical composed of a lipid raft-targeting phospholipid ether covalently bound to 131I, a beta-emitting radioisotope. Herein, we report the results of the CLOVER-WaM study [NCT02952508] in patients with previously treated WM. Methods: Eligible WM patients had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m2 on days 1 and 15 of each 57-day cycle. Dose reduction to 10 mCi/m2 was allowed in the second cycle in patients with incomplete hematologic recovery or if the expected total dose exceeded 132 mCi. Supportive care with growth factors and transfusions was permitted per treating physician discretion. The primary endpoint was major response rate (MRR, defined as partial response or better) as determined by the modified VIth International Workshop on Waldenström Macroglobulinemia Response Criteria. Secondary endpoints included overall response rate (ORR), treatment-free survival (TFS), duration of response (DOR), and clinical benefit rate (CBR, defined as stable disease or better). Efficacy endpoints were assessed in the modified intent-to-treat (mITT) population, defined as all patients who received ≥60 mCi total administered dose of iopofosine I 131. MRR was analyzed with a 95% 2-sided confidence interval (CI) using the Clopper-Pearson interval method. In this population, MRR >20% was considered statistically significant. Time-dependent efficacy endpoints were analyzed using the Kaplan-Meier method. Safety was evaluated using CTCAE v4.03 in patients who received >1 dose of iopofosine I 131. The data cut-off for this analysis was May 31, 2024. Results: In 65 patients enrolled (safety population), the median age was 70 (range, 50-88) years; 48 (73.8%) were male, and 17 (26.2%) were female. Sixty-one (93.8%) were White, 1 (1.5%) was Black/African American, and 3 (4.6%) were other or unknown. Fifty-five patients met mITT criteria and were evaluable for efficacy. The median number of prior therapies was 4 (range, 2-15). Bruton's tyrosine kinase inhibitor (BTKi) exposure was noted in 39 (71%) patients, of whom 31 (56%) were BTKi-refractory. Sixteen (29%) patients had MYD88-wild type, and 5 (9%) had CXCR4-mutated disease. The MRR was 56.4% (95% CI, 42.3-69.7). ORR was 80%; among MYD88-wild type patients, ORR was 81%, and among post-BTKi patients, ORR was 72%. CBR was 98%. The median DOR and TFS were not reached at a median follow-up of 8.8 months, with an estimated 72% of responding patients remaining progression-free at 18 months. In the safety population, any-grade adverse events, regardless of causality, were reported in 57 (87%) patients. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurring in >10% of patients included thrombocytopenia (80%), neutropenia (69.2%), anemia (44.6%), lymphopenia (13.8%), infections (12.3%), and febrile neutropenia (10.8%). Adverse event-related death occurred in 1 patient due to bacterial sepsis. Conclusion: Iopofosine I 131 demonstrated durable efficacy in previously treated WM patients, with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile across broad biologic and clinical subgroups, irrespective of risk stratification. Based on the results of this trial, iopofosine I 131 shows promise as a novel treatment for WM patients.

Abstract Background: Phospholipid ethers (PLE) provide a novel mechanism to target tumor cells. Tumor cells contain increased amounts of lipid rafts in their cell membranes, which are thought to enhance signaling and resist apoptosis. Phospholipid drug conjugates (PDC) are specifically designed to have high affinity for lipid rafts which upon binding results in trans-membrane inversion with the ability to deliver an attached therapeutic directly to the cytosol. Iopofosine I-131 (formerly identified as CLR 131) is a novel PDC delivering I-131 as a targeted tumor cell radiotherapy. Iopofosine I-131 is being examined in relapsed or refractory multiple myeloma (RRMM) patients through an open-label, Phase 2 trial, CLOVER-1 (NCT02952508). Methods: The primary objective of this study is to determine the safety and efficacy of Iopofosine I-131 in heavily pretreated MM patients. Eligibility criteria for MM patients include progression or relapsed disease that is refractory to at least 1 proteasome inhibitor and 1 immunomodulatory agent unless intolerable/ineligible to receive such agents with no upper limit to the number of prior lines of therapy. Iopofosine I-131 is administered in up to 4 IV infusions (15-20 min) over 3 months, with doses given 1-2 weeks apart each cycle for a maximum of 2 cycles, along with dexamethasone 40 mg weekly (20 mg in patients > 75), for up to 12 weeks. Following iopofosine I-131 administration, no other antineoplastic or targeted therapy was given until clinically indicated by the investigator. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the 2016 International Myeloma Working Group criteria. Results: Eleven patients with at least triple class refractory (immunomodulatory agent, proteasome inhibitor and monoclonal antibody) MM have been enrolled in this Phase 2 study with data current as of 28 May 2021. Patients had a median age of 72 (range 34-77), mean prior regimens of 7.2 (range 3-17) and received a mean total body dose of 75.4 mCi (range 59.7-118.7) of iopofosine I-131. The overall response rate (ORR) was 45.5% (5/11), the clinical benefit rate (CBR) was 72.7% (8/11) and disease control rate (DCR) was 100%. Median progression free survival (PFS) was 3.4 months. In a subset of patients who are quad/penta drug refractory, efficacy increased with an ORR of 80.0% (4/5) and CBR of 100% (5/5). The primary treatment emergent AEs in patients with MM included cytopenias (87.5%), in line with prior experience with iopofosine I-131. The most commonly observed cytopenias included Grade 3 or 4 thrombocytopenia (62.5%), anemia (62.5%), neutropenia (62.5%) and decreased white blood cell count (50%). There were no infusion-related reactions or AEs. Conclusions: Initial results for iopofosine I-131 show efficacy with a promising ORR of 45.5% and a CBR or 72.7% in heavily pretreated triple class refractory multiple myeloma patients. Interestingly, iopofosine I-131 showed its highest efficacy in patients that were quad/penta drug refractory with ORR of 80%, highlighting its potential as a later line therapy. Iopofosine I-131 is a novel cancer radiotherapeutic that may provide benefit to patients that are refractory/unresponsive to traditional MM therapies. CLOVER-1 is actively enrolling MM patients that are at least triple class refractory across the United States. Disclosures Ailawadhi: AbbVie: Consultancy; Pharmacyclics: Consultancy, Research Funding; Ascentage: Research Funding; Cellectar: Research Funding; GSK: Consultancy, Research Funding; Genentech: Consultancy; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Sanofi: Consultancy; Medimmune: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Xencor: Research Funding; Takeda: Consultancy; Beigene: Consultancy. Stiff: CRISPR: Consultancy; Gamida-Cell, Atara, Amgen, Incyte, Takeda, Macrogenetics, Eisai: Research Funding; Cellectar: Research Funding. Green: Seagen Inc.: Research Funding; bristol myers squibb: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Cellectar Biosciences: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Patents & Royalties, Research Funding; Legend Biotech: Consultancy; Neoleukin Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; SpringWorks Therapeutics: Research Funding. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Cull: Aptevo: Research Funding. Friend: Cellectar: Current Employment. Longcor: Cellectar: Current Employment. Oliver: Cellectar: Current Employment.

7561 Background: Phospholipid ethers (PLE) provide a novel mechanism to specifically target tumor cells leveraging high lipid raft content in their cell membranes. PLE/phospholipid drug conjugates are specifically designed to have high affinity to lipid rafts which upon binding results in trans-membrane flipping with the ability to deliver an attached warhead directly to the cytosol. CLR 131 (I-131-CLR1404) is a novel PLE molecule armed with I-131 resulting in targeted tumor cell radiotherapy which is being examined in relapsed or refractory WM through an open-label, Phase 2 trial, CLOVER-1 (NCT02952508). Methods: The primary objective of this study is to determine the efficacy and safety of CLR 131 in select B-cell malignancies. Eligibility criteria for WM pts include receipt of at least 2 prior treatment regimens unless ineligible to receive standard agents and have measurable disease: either IgM or extramedullary disease. CLR 131 is administered in up to 4 IV infusions (15-20 min) over 3 months. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the VIth WM Criteria for Response Assessment [Owen 2013]. Results: 6 pts with WM were enrolled in the study with data current as of 8 Jan 2021. The median age was 69 (range 54-81) with 4 females and 2 males who had a median of 2 prior regimens (range 1-5) and received a mean total body dose of 92.76 mCi CLR 131. 3 of 6 patients were MYD88 wild type (WT) of which 2 were dual WT (MYD88 WT & CXCR4 WT). The overall response rate (ORR) was 100% and the major response rate (MRR) was 83%, including 1 pt with a CR, 4 PR, and 1 MR. For those pts who were dual WT, the MRR was 100% and 1 pt who was MYD88 WT (CXCR4 is unknown) had a complete response. The median time to initial response was 48 days. Median duration of response (DOR) and treatment free remission (TFR) have not been reached; ongoing mean DOR is 335 days and mean TFR is 384 days. 100% of MYD88 WT patients have exceeded 6.5 months of follow up with average TFR of 18.1 months. The primary treatment emergent AEs in pts with WM included fatigue and cytopenias, in line with prior experience with CLR 131 in other B-cell malignancies. The most commonly observed cytopenias included Grade 3 or 4 thrombocytopenia (100%), neutropenia (83%), anaemia (66%) and decreased white blood cell count (33%). Of note, no cases of bleeding or febrile neutropenia were observed. Conclusions: Initial results for CLR 131 show efficacy across multiple WM patient genotypes including dual WT patients with durable DOR and TFR after 2 to 4 infusions. CLR 131 represents a novel and promising approach to the treatment of MYD88 WT patients who have a historical median time to progression of 1.3 years. These encouraging data led to the pivotal global CLOVER-WaM trial (N=50) in WM patients who have failed or had a suboptimal response to a Bruton Tyrosine Kinase inhibitor. CLOVER-WaM is currently enrolling. Clinical trial information: NCT02952508.

Abstract Introduction: CLR 131 (I-131-CLR1404) is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Based on preclinical and clinical experience and the radiosensitivity of MM, CLR 131 is being examined in relapsed or refractory B-cell malignancies through an open-label, phase 2 trial, CLOVER-1 (NCT02952508); initial results in pts with LPL/WM are reported here. Procedures: The primary objective of this study is to determine the efficacy and safety of CLR 131 in select B-cell malignancies. Eligibility criteria include adult pts with relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma (LPL)/Wadenstrom's macroglobulinemia (WM), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), or diffuse large B-cell lymphoma (DLBCL). Pts with LPL/WM must have received at least two prior treatment regimens unless ineligible to receive standard agents and have measurable disease: either a nodal lesion > 15 mm, an extranodal lesion > 10 mm, or measurable IgM. Prior external beam radiation therapy is allowed (< 20% of total marrow irradiated). CLR 131 is administered intravenously up to 30 minutes at total body doses (TBD) of <50 mCi, ~50 mCi, and ~75 mCi. Adverse events (AEs) are graded by NCI-CTCAE v4.03; responses are assessed by the 2012 WM Criteria for Response Assessment. Results: Four pts with LPL/WM have been enrolled in the study with data presented as of 1 Mar 2020. The median age was 70 (range 54-81) and included 2 females and 2 males who had a median of two prior regimens (range 1-5). The overall response rate was 100%, including one pt with a complete response, one pt with a partial response, and one pt with a minimal response; one pt remains under evaluation. The primary treatment-emergent AEs across all doses in pts with LPL/WM included neutropenia, thrombocytopenia, nausea, fatigue, anemia, and decreased white blood cell count, in line with experience to date with CLR 131 in other B-cell malignancies. Median time to resolution of cytopenias was 21 days. One pt received two cycles of CLR 131 with a TBD of ~100 mCi. The pt was determined to be a partial response 43 days post initial dose and a complete response at approximately 200 days; this was confirmed radiologically 406 days post initial dose. The duration of response for this pt is currently at 25 months and is ongoing. One pt received ~ 50 mCi CLR 131 and saw an 89% decrease in IgM at 64 days post infusion. One pt received ~ 75 mCi CLR 131 and had a 45% decrease in IgM at 64 days post infusion. One pt received two cycles of CLR 131 with a TBD of ~150 mCi, experiencing a 48% reduction in IgM to date and has not yet completed the evaluation period. Conclusions: CLR 131 is a unique, first-in-class targeted radiotherapeutic in development for multiple B-cell hematologic malignancies. The observed positive signals of efficacy and safety from this preliminary data in relapsed or refractory LPL/WM pts is encouraging and will be further explored. Citation Format: Sikander Ailawadhi, Jarrod Longcor, Kate Oliver, Igor D. Grachev. CLR 131 demonstrates 100% overall response rate in relapsed or refractory lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM): initial results from ongoing phase 2 trial, CLOVER-1 study [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-25.

Background: CLR 131 is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Based on initial preclinical and clinical experience and the radiosensitivity of MM, fractionated dosing of CLR 131 is being examined in RRMM in a Phase 1 trial (NCT02278315) and a Phase 2 trial, CLOVER-1 (NCT02952508). Methods: Both the Phase 1 and Phase 2 trials of CLR 131 aim to determine efficacy and safety in RRMM. Eligibility criteria include progressive or relapsed MM that is refractory to at least 1 proteasome inhibitor (PI) and 1 immunomodulatory (IMiD) drug with no upper limit to the number of prior lines of therapy. Prior autologous stem cell transplant (ASCT) and external beam radiation therapy are allowed (< 20% of total marrow irradiated). The Phase 1 trial was a single and fractionated ascending dose escalation safety study and the Phase 2 trial is evaluating 3 doses: a bolus dose and 2 fractionated doses. The fractionated doses of CLR 131 included infusion of either 31.25 mCi/m2 CLR 131 or 37.5 mCi/m2 CLR 131 (administered as 15.625 mCi/m2 or 18.75 mCi/m2, respectively, on day 1 and day 7 (± 1 day)) administered as a 30-minute intravenous infusion is reported here. Adverse events (AEs) are graded by NCI-CTCAE v4.03. Responses were determined using IMWG criteria as assessed by the investigator. Results: As of 30Jul2019, 10 subjects have received fractionated 31.25 mCi/m2 and 6 subjects fractionated 37.5 mCi/m2 CLR 131. In addition, 1 subject was scheduled to receive fractionated 37.5 mCi/m2 CLR 131 but died due to progressive disease prior to administration of the second dose; this subject is not included in the analyses below as they did not receive both fractionated doses. There is no upper age limit for enrollment and the median age for the 16 RRMM patients was 71 (range 51-83), including 6 females and 10 males with a median of 4 prior therapies (range 2 to 13). Seven patients had prior ASCT. CLR 131 demonstrated 100% disease control rate in subjects receiving either fractionated dose of CLR 131. The overall response rate (ORR) in the fractionated 37.5 mCi/m2 cohort is 50%. Three subjects in the cohort experienced a partial responses (PR), median time to response 43 days, and the other three had minimal responses (MR) with an average 39% reduction in m-protein. In this cohort, 80% of the subjects were either quad- or penta-refractory; all 80% were refractory to daratumumab. There were two subjects in the 31.25 mCi/m2 cohort with non-secretory disease and their status was followed by FDG-PET imaging. Both have been excluded from the evaluation of efficacy as their disease does not meet with IMWG criteria for response. No patients in this cohort achieved a PR or better however a majority of the subjects experienced a minimal response. The primary AEs include thrombocytopenia, anemia, neutropenia, and fatigue (Table 2). The hematologic AEs were expected, manageable and followed a predictable timeline to nadir (average. 40 days) and subsequent recovery (average 17 days post nadir). Conclusions: CLR 131 is a unique, first in class targeted radiotherapeutic for RRMM. Preliminary data for CLR 131 administered as a fractionated dose shows an acceptable and expected safety profile in this patient population. Fractionated dosing at 37.5 mCi/m2 has shown an efficacy signal and has been adopted as the standard for CLR 131 dosing in ongoing and future trials. Dose escalation to determine the highest tolerated dose is ongoing in the Phase 1 study and is currently examining a fractionated infusion of 40 mCi/m2 administered as 20 mCi/m2 CLR 131 on day 1 and day 7 (± 1 day). Based upon these data enrollment to the fractionated 37.5 mCi/m2 cohort of the Phase 2 trial continues. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Stiff:Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding. Ibrahim:Cellectar: Honoraria, Research Funding; Incyte: Research Funding; Pfeizer: Research Funding; Puma: Research Funding; Eli Lilly: Research Funding; Hoffman-LaRoche: Research Funding; Spectrum: Research Funding; Takeda: Research Funding. Cull:Celgene: Speakers Bureau; ADC Therapeutics: Research Funding. Green:GSK: Consultancy; Seattle Genetics: Research Funding; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Oliver:Cellectar Biosciences: Employment. Longcor:Cellectar Biosciences: Employment, Equity Ownership.