ALBERT

Description: INTRODUCTION: Innate immune sensors such as TLR2 are consistently overexpressed in bone marrow CD34+ cells from low risk MDS patients (pts), and a gain of function mutation in TLR2 correlates with progression. Ex vivo inhibition of TLR2 in cultures of CD34+ cells using Tomaralimab (OPN-305), a fully humanised antagonistic IgG4 monoclonal antibody, led to an increase in differentiation of erythroid cultures. We previously reported a human trial with Tomaralimab in low risk/Int-1 MDS that failed HMA therapy (HMA-F) using 5 mg/kg Tomaralimab (n=11), with 4 pts treated at a higher dose of 10 mg/kg monthly. Here we report response data in an expanded 10 mg/kg HMA-F cohort. Tomaralimab was administered as a third line therapy to heavily pre-treated transfusion-dependent (TD) pts with 〉50% of pts having received ≥4 previous therapies. The data indicate that Tomaralimab is a potential therapy for low risk/Int-1 MDS. METHODS: We designed a phase I/II multi-site clinical trial of Tomaralimab for pts with low or Int-1 risk MDS after failure with prior therapy with HMA. Pts were treated every 4 weeks for up to 9 cycles, with the potential of continued use thereafter. Azacitidine (AZA) could be added back into the therapy regimen after 16 weeks of Tomaralimab monotherapy if there was no response. The primary endpoint was the induction of transfusion independence for two consecutive cycles as defined in IWG criteria (major responders). A minor response was characterised by at least a 50% reduction in the need for transfusions compared to their transfusions prior to Tomaralimab therapy. We also evaluated the toxicity, pharmacokinetic profile, receptor occupancy, cytokine profile, as well as a novel set of TLR2 related genes. RESULTS: At the time of this report, 51 pts have received Tomaralimab at 10 mg/kg in HMA-F pts. The median age was 72 years and 79% of the pts were male. Twenty two pts were fully evaluable, having completed the study at Week 36 and either achieving transfusion independence or, if not, receiving AZA add-back unless previously withdrawn due to toxicity or disease progression. Pre-study, the average transfusion was 10 units (median = 3.5 units) and the average on-study was 2 units (median = 1.5 units). Even though these pts were very heavily pre-treated with previous therapies, there were 6 pts who met the primary endpoint (27%) across multiple centres, 5 of which were on Tomaralimab monotherapy at the time of response. Furthermore, there were 5 minor responders (23%), giving an overall response rate (ORR) of 50%. Additionally, 10 pts (45%) remained stable throughout the therapy window. There were no dose limiting toxicities or development of anti-drug antibodies. Tomaralimab receptor occupancy (RO) was measured by flow cytometry in both the BM (CD34+CD38- cells) and PB (CD14+ CD45+). Measured RO levels in both indicated that there was full receptor occupancy in both compartments and that Tomaralimab penetrated the BM. Compared to non-responders, there was a non-significant increase in the expression of TLR1, IRAK4, IL-6, GATA-2, CD71, TRAF6 and S100A9 and a non-significant decrease in GATA-1, TLR2 and TLR6. These are non-significant because of low numbers in the non-responder group. Gene expression was increased in all cases relative to age matched non-MDS healthy controls. Of these genes, of particular interest is S100A9. This has been shown in the literature to be increased in the BM plasma of MDS pts. Furthermore, using the cell line THP-1XBlue we showed that S100A9 signals via TLR2 in vitro and this effect was ameliorated by incubation with Tomaralimab. CONCLUSIONS: Early data suggest that Tomaralimab therapy presents a novel and safe treatment for heavily pre-treated low risk/Int-1 MDS HMA-F pts. Tomaralimab exhibited a 50% ORR in heavily pre-treated, transfusion dependent HMA-F patents. Treatment was well tolerated and penetrated the bone marrow. RO in the blood could also be used as a surrogate for RO in the bone marrow. Surprisingly, there was no correlation between efficacy and cytokine concentration in the plasma, although cytokine changes in the bone marrow were not determined. There were however non-significant alterations in TLR2 and related genes in purified bone marrow cells from pts. Studies using these cells are underway to further elucidate the mechanism of action. In brief, Tomaralimab therapy presents a potential therapeutic option for heavily pre-treated low risk pts that have failed HMA therapy. Disclosures Jabbour: novartis: Research Funding. Konopleva:cellectis: Research Funding; abbvie: Research Funding; Immunogen: Research Funding; Stemline Therapeutics: Research Funding. Daver:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Novartis: Consultancy; ARIAD: Research Funding; BMS: Research Funding; ImmunoGen: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy; Alexion: Consultancy; Incyte: Consultancy; Sunesis: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Consultancy; Kiromic: Research Funding; Karyopharm: Consultancy; Karyopharm: Research Funding. DiNardo:Agios: Consultancy; Bayer: Honoraria; Karyopharm: Honoraria; Abbvie: Honoraria; Medimmune: Honoraria; Celgene: Honoraria. Bose:Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; CTI BioPharma: Research Funding. Komrokji:Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding. Roboz:AbbVie: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Sandoz: Consultancy; Celltrion: Consultancy; Pfizer: Consultancy; Astex Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Argenx: Consultancy; Cellectis: Research Funding; Celgene Corporation: Consultancy; Cellectis: Research Funding; Orsenix: Consultancy; Daiichi Sankyo: Consultancy; Janssen Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Aphivena Therapeutics: Consultancy; Celgene Corporation: Consultancy; Orsenix: Consultancy; Astex Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Argenx: Consultancy; Daiichi Sankyo: Consultancy; Celltrion: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Novartis: Consultancy. Miller:Opsona Therapeutics: Employment. Arbe-Barnes:Opsona Therapeutics: Employment. Reilly:Opsona Therapeutics: Employment. McGuirk:Opsona Therapeutics: Employment. Kearney:Opsona Therapeutics: Employment. Keogh:Opsona Therapeutics: Employment.

Description: INTRODUCTION: Alterations of innate immune signaling, including overexpression of TLR2, are common in MDS. Signaling mediated by this receptor results in activation of NF-kB and the histone demethylase JMJD3 (KDM6B) leading to expression of multiple cytokines that can result in inhibition of hematopoiesis. Significant TLR2 overexpression in MDS bone marrow CD34+ cells, especially after HMA therapy, has been reported (Wei, Leukemia 2013). OPN-305 is a fully humanized antagonistic IgG4 kappa monoclonal antibody to TLR2 which significantly increases the formation of erythroid colonies (CFU-E) in BM CD34+ cells isolated from pts with lower-risk MDS in vitro. This data suggested the potential therapeutic value of OPN-305 in patients (pts) with MDS. METHODS: We designed a phase I/II trial of OPN-305 for pts with Low or Int-1 risk MDS by IPSS after failure to prior therapy with a HMA. Pts with isolated del(5q) should have received therapy with lenalidomide. Pts with prior history of AML or alloSCT were excluded from the study. Because, OPN-305 had not been previously used in pts with hematological malignancies, the study had an initial phase of N=10 pts using OPN-305 at a dose of 5 mg/kg every 4 weeks for a maximum of 9 cycles. Therapy could be repeated as long as there was no excess toxicity or progression. If after 16 weeks of therapy, there was no response, azacitidine on a 3 day schedule, could be added to OPN-305. Responses were evaluated following the revised 2006 IWG criteria. This initial cohort allowed evaluation of toxicity, pharmacokinetic analysis, receptor occupancy, and sequential analysis of cytokine profile. Depending on results, dose escalation to 10 mg/kg monthly could be instituted in a second cohort of N=5 pts. RESULTS: At the time of this report, 15 pts have been enrolled, 11 at the initial 5 mg dose and 4 at 10 mg/kg. All pts were evaluable for toxicity and 12 (80%) were evaluable for response. Patient characteristics are shown in Table 1. Median age was 73 years (range 48-87). Three (20%) pts were classified as Low risk and 12 (80%) as Intermediate-1 risk by IPSS. Seven pts had normal karyotype, 2 del(5q), 2 trisomy 8, 1 del(20q), 1 monosomy Y and 2 other single or double abnormalities. Median number of prior therapies was 2 (range 1-4) with a median duration of prior therapies of 28 months (range 4-62) (Figure 1). A total of 13 (87%) pts were transfusion dependent of red cells prior to enrollment. Median follow up is 8 months (1-16). Median number of cycles administered is 5 (2-17) with 5 (33%) pts having received addition of azacitidine after 16 weeks of therapy. A total of 5 (42%) pts developed AEs related to OPN-305. All AEs were grade 1 with gastrointestinal disorders being the most frequent (33%). At this point, no significant drug related toxicity has been documented with no excess infectious complications. Overall response rate in the form of hematological improvement was 50% (6/12) with 2 (17%) pts achieving transfusion independence. A total of 5 (33%) pts remain on study with 3 pts continuing on therapy off study. Three (20%) pts were taken off study due to progression to AML and 4 (27%) due to no response. Half-lives of OPN-305 in serum were 〉200 h at 5 mg/kg and 〉300 h at 10 mg/kg (Figure 2A). There was a greater-than-dose proportional increase in mean OPN-305 exposure (AUC) between 5 and 10 mg/kg. PK profiles after repeated dosing at 5 mg/kg in N=2 subjects and pre-dose (trough) levels in other subjects indicated some variability in the potential for accumulation. TLR-2 receptor occupancy in blood PBMCs and bone marrow aspirates was essentially complete in virtually all samples taken after OPN-305 administration (Figure 2B). There is no evidence of treatment related anti-drug antibodies. Compared with baseline, no statistically significant dynamic changes of IL-23, IL-18, IFN-r, IL-10, IL-1β, IL-6, IL-12 (p40), IL-12 (p70) and IL-8 levels where observed after treatment, among responders or non-responders or based on OPN-305 dosing. CONCLUSIONS: Treatment with OPN-305 in pts with previously treated lower-risk MDS was well tolerated with no significant toxicities and 50% ORR. Correlative studies suggest adequate receptor occupancy with no correlation between responses and cytokine levels. Because no effect on cytokine profile, we plan to continue to escalate the dose of OPN-305 and investigate its activity profile in front line therapy. Table 1. Table 1. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures DiNardo: Daiichi Sankyo: Research Funding; Agios: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding.