Cull, Elizabeth H.

INTRODUCTION: Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. In prior studies, LUX has been shown to suppress aberrant proliferative signaling in B cell malignancies and acute myeloid leukemia (AML) via regulation of BTK, LYN, SYK, AKT, ERK, and MAPK. LUX is cytotoxic to primary AML cells insensitive to other FLT3 inhibitors and to malignant B-cells insensitive to ibrutinib, at pM and nM concentrations, respectively. AIMS: The primary objectives of these studies are to assess the safety, tolerability, and pharmacokinetics (PK) of LUX and determine recommended phase 2 doses for relapsed or refractory (R/R) AML and B cell malignancy patients. METHODS: In two studies (NCT04477291; NCT03893682), LUX (original formulation, G1) was administered continuously as oral capsules BID in 28-day cycles of ascending cohorts (relapsed or refractory de novo, secondary, or therapy-related AML or higher risk myelodysplastic syndrome (MDS), and relapsed and refractory for B cell lymphoma and chronic lymphocytic/small lymphocytic leukemia). A novel generation 3 (G3) formulation of LUX designed to increase bioavailability was tested at a single-dose (sub-study) for relative bioavailability (RBA), followed by continuous dosing in subsequent R/R AML patients. RESULTS: In the B-cell study (as of 15 th May 2023), LUX has been administered to 36 patients at dose levels from 150 mg to 900 mg BID in patients with a median of 3 lines of prior treatment, with 47.2% having received a BTK-inhibitor. Only one (2.8%) patient had a DLT of hypertension and 14 (38.9%) experienced at least one drug related ≥Grade3 treatment emergent adverse event (TEAE). Two patients (900 mg) are currently on study with no DLT and no ≥Grade 3 related TEAEs. A Follicular lymphoma patient is at cycle 28, and achieved a best response as partial response (PR) with a decrease in lesion size of 76.2%; an SLL patient is at cycle 13, and achieved stable disease (SD) showing a decrease in lesion size of 43.1% (Figure A). The overall best response achieved among the 17 patients who have been on treatment for more than 12 weeks are stable disease (SD) (n=11), partial response (PR) (n=3), minor response (n=2) and complete response (CR) (n=1). As of 5 th June 2023, in the AML trial, a total of 40 patients (16 (40%) FLT3-ITD, 21 (52.5%) FLT3-WT, 2 (5.0%) FLT3-TKD, and 1 (2.5%) unknown mutations) with a median of 3 prior treatments (range, 1 - 10) have been treated with LUX G1 formulation at dose levels from 450 mg - 900 mg BID (n=34) or with 50 mg BID of G3 formulation (n=6). Four (10%) experienced drug related SAE and 7 (17.5%) had a drug related grade ≥3 TEAEs. The most common related TEAEs were lymphocyte count decrease, platelet count decrease, and anemia (n=2; 5% patients each). One (2.5%) patient at 450 mg dose, reported complete remission without minimum residual disease (CRmrd) and remained on study for 56 weeks. In the RBA sub-study, G3 (50 mg) produced comparable exposures to G1 (450-900 mg range) (Figure B) and was, therefore, selected as the starting dose for use in the R/R AML study. Six patients were treated with a continuous dosing of 50 mg BID G3; with plasma levels of 274 ng/mL and 195 ng/mL LUX observed by the end of C1D15 and C1D22 respectively. No drug related Grade ≥3 TEAEs or DLTs were observed in 50 mg BID G3 LUX treated patients; with no new safety signals observed for the G3 formulation. Based on these findings and expected exposures for higher dose levels, the cohort safety review committee has approved escalation of G3 dosing to 200 mg BID at which dosing is ongoing. CONCLUSIONS: LUX has a favorable safety profile in patients at all tested dose levels, for multiple cycles, for both studies. Antitumor activity was observed in a heavily pretreated relapsed AML patient and in multiple B-NHL subtypes and CLL/SLL patients including several with prior ibrutinib exposure. Continuous dosing of patients with R/R AML and Higher-Risk MDS with the G3 formulation is ongoing; with updated clinical data (200 mg dose level) to be presented at the meeting.

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.

Abstract INTRODUCTION: Luxeptinib (CG-806) is a potent, non-covalent oral inhibitor of BTK and FLT3. It suppresses BCR signaling pathways (LYN, SYK, BTK, AKT, ERK) and other oncogenic pathways in cell lines and primary CLL cells, kills malignant B-cells insensitive to ibrutinib or venetoclax at low nM concentrations, and shows enhanced activity in combination with venetoclax. Luxeptinib is currently being evaluated in a Phase 1a/b trial in patients with relapsed or refractory B-cell malignancies (NCT03893682). AIMS: Primary objectives are to assess the safety and tolerability of luxeptinib and determine the recommended expansion dose for future clinical trials in patients with R/R CLL/SLL or B-NHL. Key secondary objectives include elucidation of the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and evidence of antitumor activity. METHODS: Luxeptinib is administered continuously as oral capsules BID in 28-day cycles, in ascending cohorts of 3 patients. Treatment emergent adverse events (TEAEs) and tumor responses are evaluated per disease specific guidelines. RESULTS: As of June 7, 2021, a total of 23 patients (median age 64.0 years, 11 CLL/SLL, 4 follicular lymphoma (FL), 1 Richter's transformation lymphoma, 2 Waldenstrom's macroglobulinemia (WM), 2 mantle cell lymphoma, 3 diffuse large B cell lymphoma (DLBCL)) with a median of 3 prior systemic regimens (range of 1 - 12) have been treated with luxeptinib at doses of 150 mg (n=1), 300 mg (n=1), 450 mg (n=9), 600 mg (n=4) and 750 mg (n=8). Drug related grade ≥ 3 TEAEs included neutropenia (n=5, 21.7%), leukocytosis (n=2, 8.7%), decreased white blood cell count, decreased platelet count, anemia, increased alanine aminotransferase, diarrhea, hypertension, and headache (n=1, 4.3 % each). One patient, who experienced progressive hypertension before receiving luxeptinib, developed grade 1 hypertension during screening evolving to grade 2 prior to dosing on C1D1, experienced grade 4 hypertension after luxeptinib treatment at 750 mg BID for 5 days. While this was considered a DLT per protocol, luxeptinib plasma levels in this patient were lower than those observed in patients at this and lower dose levels, and no drug-related hypertension has been observed in any other patient treated to date. The average steady-state (C min) plasma levels of luxeptinib in patients treated with 750 mg BID were > 1µM and were sustained over multiple cycles. PD analysis demonstrated that C min of luxeptinib in the plasma of patients treated with doses of 300 mg or higher significantly reduced levels of phosphorylated BTK, SYK, ERK and FLT3 in EOL-1 reporter cells in a plasma inhibitor activity assay, demonstrating multi-target engagement. Response evaluations were available for 12 patients who had at least one imaging study or IgM measurements (WM patients) after starting treatment. Eight out of these 12 patients had various reductions of lesion size or IgM measurements compared to baseline (3 SLL, 2 FL, 1 CLL, 1 WM and 1 DLBCL), demonstrating anti-tumor activity. FDG PET-CT scans in one FL patient, who had 2 prior regimens, revealed lesion growth during treatment with luxeptinib at 450 mg BID for 7 cycles. After dose-escalation to 600 mg BID in Cycle 8, lesion measurements demonstrated continuous reduction. By C15D1, target lesions decreased by 42.5% and 11.3% when compared with peak tumor size and baseline measurements, respectively. One WM patient in Cohort 5 (750 mg BID), who had 2 prior regimens including ibrutinib, has had a 24.9% reduction in IgM level by C3D1 compared with baseline as her best response so far. CONCLUSIONS: Luxeptinib has a favorable safety profile in patients treated with 150 mg to 600 mg BID over multiple cycles. A single apparent DLT (grade 4 hypertension in one patient with pre-existing hypertension) led to expansion of the 750 mg dose level to 6 patients. Pharmacodynamic studies documented inhibition of SYK, BTK and ERK in the BCR signaling pathway. Anti-tumor activity was observed in multiple B-NHL subtypes and CLL/SLL patients. Enrollment of patients with R/R CLL/SLL and B-NHL at dose level 5 (750 mg) is ongoing and updated clinical data will be presented at the meeting. Disclosures Samaniego: Arog: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees. Burke: AstraZeneca: Consultancy; Verastem: Consultancy; Bristol Myers Squibb: Consultancy; Epizyme: Consultancy; Kura: Consultancy; Kymera: Consultancy; SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy; Beigene: Consultancy, Speakers Bureau; AbbVie: Consultancy; MorphoSys: Consultancy; Roche/Genentech: Consultancy. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Cherry: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sadiq: Dava Oncology: Honoraria. Reid: ADC Therapeutics: Other: Serves as Principle Investigator, Research Funding; Aptose Biosciences: Other: Serves as Principle Investigator, Research Funding; Millennium Pharmaceuticals: Other: Serves as Principle Investigator, Research Funding; Xencor: Other: Serves as Principle Investigator, Research Funding. Roeker: TG Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company; Pharmacyclics: Consultancy. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Benbatoul: Aptose Biosciences, Inc.: Current Employment. Haney: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Bejar: Astex: Consultancy; Silence Therapeutics: Consultancy; Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Epizyme: Consultancy, Honoraria; Takeda: Research Funding; Gilead: Consultancy, Honoraria; BMS: Consultancy, Research Funding.

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.