Abstract Over the past decade, significant improvements in survival outcomes have been experienced by multiple myeloma (MM) patients. However, MM remains an incurable disease and patients with triple-class refractory MM have limited treatment options and a dismal prognosis. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has transformed the treatment algorithm of relapsed/refractory MM (RRMM), with high overall response rates. Nevertheless, a significant proportion of patients ultimately relapse despite achieving deep remission and show poor outcomes with subsequent treatment post anti-BCMA immunotherapies.1 Iopofosine I-131 (iopofosine) is a first-in-class phospholipid ether radio-conjugate that targets lipid raft microdomains on tumor cells and is internalized. Here we present seven cases of triple class refractory MM patients that relapsed or were refractory to anti-BCMA immunotherapy and treated with iopofosine plus low dose dexamethasone (LoDEX). Patient received a single fractionated cycle of 30mCi/m2 of iopofosine (15 mg/m2 dosed day 1 and day 15) and received LoDEX (40 mg/week for 12 weeks) with an optional second cycle of iopofosine approximately 60 days later. Six of the seven patients achieved the minimum required total administered dose of 60 millicuries (mCi) to be in the evaluable population and 50% achieved a partial response (PR) or better.

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. DisclosuresAilawadhi: 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.

Phospholipid ethers (PLE) provide an innovative approach to preferentially target cancer cells by capitalizing on their increased number/size of lipid rafts. PLE are designed to possess high affinity to lipid rafts which upon binding results in internalization and the ability to deliver an attached warhead to the cytosol. CLR 131 is a novel PLE conjugated to I-131, which was chosen due to its 8-day half-life and well-established efficacy in multiple cancer types. Preclinical/phase I data has shown CLR 131 to be preferentially taken up by cancer cells and to cross the blood brain barrier.

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.

BACKGROUNDCLR 131 is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers by malignant cells. CLR 131 selectively delivers radiation to malignant tumor cells, thus minimizing radiation exposure to normal tissues.OBJECTIVECLR 131 is being examined in a Phase 1 trial, CLOVER-2 (NCT03478462), to determine the safety, tolerability, and initial efficacy of CLR 131 in children and adolescents with relapsed/refractory malignancies.METHODSEligibility criteria include children with relapsed or refractory solid tumors or malignant brain tumors for which there are no standard treatment options with curative potential. Subjects must be between ages 2 and 21 with no limit to the number of prior therapies. CLR 131 is administered as a single infusion in escalating doses beginning at 15 mCi/m2. Adverse events (AEs) are graded by NCI-CTCAE v5.RESULTSAs of 10Jan2020, four subjects with brain tumors have received CLR 131; one at 15 mCi/m2 and three at 30 mCi/m2. Diagnoses included DIPG (2), glioblastoma (1), and medulloblastoma (1). Median age is 13 years (range 10–15) and patients received a median of two prior therapies (range 1 to 8). There were no treatment emergent AEs at the 15 mCi/m2 dose level attributed to CLR 131 by the investigator. Assessment of the 30 mCi/m2 dose level is ongoing.CONCLUSIONSCLR 131 is a unique, first in class targeted radiotherapeutic for pediatric malignancies. Preliminary data shows an acceptable and expected safety profile in this patient population. Dose escalation to determine the highest tolerated dose is ongoing.

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.

Abstract Purpose: Breast cancer (BrCa) is the most common invasive cancer in women globally and the second most common cause of death from cancer in women in the US. Combretastatin A-4 (CA4) and associated analogues have been shown to be potent cytotoxins and inhibitors of tumor blood flow. However, CA4 and its analogues have not progressed rapidly through clinical trials. It has been shown that with some of the CA4 analogues, incomplete disruption of the vasculature and/or proangiogenic factors around the tumor result in survival of the cap portion of the tumor and future progression. Additionally, the over expression of MDR-1 gene which encodes for P-glycoprotein (Pgp) efflux pumps which is overexpressed in many cancer cells has been shown to limit the activity of these molecules. Phospholipid-drug conjugates (PDCs) are a modality designed to selectively deliver molecules to the tumor or tumor microenvironment, significantly increasing intracellular or local concentrations. In the current study, we established a series of PDCs using a single CA4 analogue (CA4A) conjugated to our phospholipid ether targeting platform (PDC-CA4A) utilizing different peptide linkers that allow for facile targeting and release of the CA4A payload. In this study, we evaluated the in vitro and in vivo therapeutic potential of different PDC-CA4A molecules. Methods: In vitro assessment of cellular internalization, accumulation and release of the payload was evaluated via mass spectrometry in A549 and normal human dermal fibroblast (NHDFs) cells. Additionally, in vitro assessment of cytotoxicity was performed in A549, MCF7, HCT116 and NHDFs with fifty percent inhibitory concentrations (IC50s) being determined for each. Subcutaneous HCT116 and MCF7 xenograft tumor models were used to evaluate the antitumor efficacy of several PDC-CA4A molecules compared with the free CA4A molecule. Results: All PDC-CA4A molecules showed excellent uptake, accumulation and release of the CA4A payload in the A549 cell line. Uptake was detected at the first time point tested (30 minutes) after exposure and continued through 24 hours. A steady state of release of the payload and new PDC-CA4A molecules entering the cell was reached 3 hours post exposure. Cytotoxicity tests demonstrated IC50s ranging from nanomolar to micromolar concentration depending upon the linker being utilized. In vivo, PDC-CA4A-109 (specific molecule) demonstrated statistically significant benefit over both free CA4A and the positive control group. Conclusion: Our results suggest that PDC-CA4A-109 is a promising antitumor agent to treat both breast cancer and colorectal cancers. Further clinical study is warranted to evaluate the safety and feasibility of PDC-CA4A-109 as a novel targeted therapy. Citation Format: Jarrod Longcor, Randall Hoover, Mark Wolf. Preclinical evaluation of a novel phospholipid drug conjugate with a combretastatin A-4 analogue for improved breast cancer therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-21.

Abstract Lipid rafts (LR) are specialized regions or microdomains within the cell membrane that are highly enriched with cholesterol and sphingolipids. The presence of LR in tumor cell membranes is as much as 10 fold higher than in normal tissue. Our phospholipid ether (PLE) molecules [18-(p-iodophenyl)octadecyl phosphocholine] have a high affinity for binding and being transported into cells via LRs(1). In this study, we report the development of CLR 180099, a LR targeting phospholipid-drug conjugate (PDC), consisting of a PLE with a cleavable peptide linker (non-cathepsin cleavage) bound to a flavagline (FLV) analogue, a highly potent inhibitor of cell proliferation and simulator of apoptosis. We first study the presence of LR on a large panel of cancer cell lines. Then, we evaluated the uptake of multiple PLE conjugates in a similar panel of cancer cell lines. Then CLR 180099 was assessed for uptake and the release of the FLV in in vitro tumor cell lines. Finally, we present a series in vitro anti-proliferation assays in multiple cell lines and in vivo tolerability as compared to free FLV and efficacy of CLR 180099 in HCT 116 colorectal cancer xenograft. Presence of LR was found to be determinant in the sensitivity of tumor cells to the cytotoxic effect of the PDC. Importantly, CLR 180099 demonstrated significant improvement in tolerability of FLV versus free FLV. These results suggest that PLEs could be used to make PDCs that improve tolerability and efficacy of the warhead molecule. The ability to specifically deliver a variety of warheads/payloads to a broad range of tumor cells offers a unique advantage of PDCs. These findings support the continued development of CLR 180099 PDC as a novel targeted therapy. The PDC described in this abstract is investigational, as efficacy and safety have not been established. There is no guarantee that this PDC will be available commercially. Citation Format: Jarrod Longcor, Anatoly Pinchuk, Randall Hoover, John Friend. CLR 180099, a lipid raft targeted phospholipid-drug conjugate, shows potent improved safety and efficacy against colorectal tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C070. doi:10.1158/1535-7163.TARG-19-C070

Background: CLR 131 [18-(p-[131I]-iodophenyl)octadecyl phosphocholine] is an investigational, radioiodinated cancer therapy that exploits the selective uptake and retention of phospholipid ethers (PLEs) and PLE analogs by malignant cells [Mollinedo 2010, Weichert 2014]. To produce CLR 131, the core PLE analog is radioiodinated with the radioisotope iodine-131 (I-131). CLR 131 provides targeted delivery of radiation to malignant tumor cells, thus minimizing radiation exposure to normal tissues. The mechanistic basis for the cancer-cell selective uptake involves interaction with lipid raft regions of the plasma membrane. Imaging studies with CLR 124 [18-(p-[124I]-iodophenyl)octadecyl phosphocholine], which is chemically and structurally identical to CLR 131, have demonstrated cancer-cell selective uptake and retention in all but 3 of over 60 tumor cell models assessed to date [Weichert 2014]. Using a MM1.S myeloma xenograft murine model, highly selective uptake of CLR 124 was documented using I-124 PET imaging (Figure 1). Similarly, using CLR 124 in a disseminated MM1.S myeloma model, PET-CT documented selective uptake of CLR1404 in anatomic regions of dense myelomatous involvement (Figure 2). CLR 131 activity was assessed in NOD scid gamma mice bearing 200 mm3 MM1.S flank tumors who received a single tail vein injection of CLR 131 (100 µCi) or a mass equivalent dose of CLR1404. As anticipated, a single dose of CLR 131 produced tumor growth delay (Figure 3). Study Design and Methods: This Phase 1 trial (NCT02278315) is assessing CLR 131 in patients with relapsed or refractory multiple myeloma (RRMM). The primary objective is to determine the safety and tolerability of CLR 131 as a single or multiple dose, with and without concurrent weekly dexamethasone, in patients with RRMM who have previously been treated with, or are intolerant of, an immunomodulator and a proteasome inhibitor. Secondary objectives include identifying the recommended Phase 2 dose and schedule, and determining therapeutic activity. Eligibility criteria include progressive, RRMM, and at least one previous exposure to proteasome inhibitor and immunomodulatory drugs with no limit to the number of prior lines of therapy. Patients are to have at least 5% plasma cell involvement and measurable disease (by m-protein or FLC, although non-secretors are considered on a case-by-case basis). Patients are excluded if they have had prior radioisotope therapy, prior total body or hemi-body irradiation, or prior external beam radiation therapy resulting in greater than 20% of total bone marrow receiving greater than 20 Gy. Patients receive CLR 131 as a fractionated infusion of CLR 131 at increasing doses administered on day 1 and day 7 (± 1 day) as a 30-minute intravenous infusion with 40 mg concurrent weekly dexamethasone. All patients take thyroid protection medication starting the day prior to CLR 131 infusion and continuing for 14 days after the last CLR 131 infusion. Following the CLR 131 infusions, patients are followed for a total of 12 weeks to assess safety and efficacy. At least 3 to 4 patients are enrolled in each dose level. Patients who discontinue prior to the day 64 assessment can be replaced. A Data Monitoring Committee evaluates each dose level for safety and tolerability and provides recommendations for dose escalation, de-escalation, or expansion. Current Status As of 31-Jul-2019, 28 subjects have been enrolled; 18 patients received a single infusion of CLR 131 and 10 patients have received fractionated doses of CLR 131. Enrollment in the 40 mCi/m2 fractionated dose level is ongoing. Disclosures Longcor: Cellectar Biosciences: Employment, Equity Ownership. Oliver:Cellectar Biosciences: Employment.