Lunin, Scott D.

Background: Guadecitabine is a next generation subcutaneous (SC) hypomethylating agent (HMA) resistant to degradation by cytidine deaminase which results in prolonged in vivo exposure to the active metabolite decitabine. We conducted a phase 2 study of guadecitabine in 102 Myelodysplastic Syndromes (MDS), and Chronic Myelomonocytic leukemia (CMML) patients. International guidelines recommend a minimum of 4 to 6 cycles of HMA treatment to gain maximum benefit, but some suggest that treatment may not be beneficial if no response was observed after 4 cycles. No prospective studies have confirmed the correlation between an HMA number of cycles with response and survival using landmark methodology. We present here the results of landmark response and survival analyses based on number of cycles and whether patients had an objective response or not. M ethods: Landmark response based on 2006 IWG criteria, and overall survival (OS) analyses for patients alive at or beyond month 3 and month 5 (time of planned start of cycle 4 and cycle 6 respectively) were conducted. Objective response (OR) was defined as patients who had Complete Response (CR), Partial Response (PR), marrow (m)CR, or Hematological Improvement (HI). Landmark OS was compared between patients who received at least 4 or 6 cycles and those who did not. The landmark methodology avoids the bias of early deaths before cycles 4 and 6 attributing a survival benefit in those who did not die early and were able to get more cycles. We also compared the result in responding and non-responding patients to see if survival benefit was restricted to responding patients only. Results: The study completed enrolment with 102 patients: 53 patients after HMA failure (relapsed/refractory or r/r), and 49 HMA-naive patients (Treatment Naïve or TN) with a median follow up for the entire study of 3.2 years (IQR 2.9-3.5 years). Median age was 71 and 72 years for TN MDS/CMML and r/r MDS/CMML patients respectively. Median OS was 23.4 months (m) for TN MDS/CMML patients and 11.7 m for r/r MDS/CMML patients. Of the 102 patients treated, 37 patients (36.3%) and 58 (56.9%) received less than 4 and 6 cycles respectively. The landmark analysis population was 91 patients for the 4-cycle analysis and 87 patients for the 6-cycle analysis. In those patients, the primary reasons for treatment discontinuation before cycle 4 or 6 respectively were patient decision (9.8% and 11.8%), and investigator decision (5.9% and 9.8%) while early progression accounted for 3.9% and 10.8% of those patients. There were no major baseline characteristics difference between patients who received at least 4 and 6 cycles and those who did not in the patients included in the landmark analyses. In the landmark analysis, patients who received at least 4 cycles (65 patients) had an OR rate of 68% compared to 15% in 26 patients who received <4 cycles (p <0.0001) and median OS of 20.4 m compared to 15.2 m respectively (HR 0.78, 95% CI 0.45-1.3, p 0.36). Those who received at least 6 cycles (44 patients) had an OR rate of 82% compared to 26% in 43 patients who received < 6 cycles (p<0.0001), and median OS of 23.8 m vs 13.6 m respectively (HR 0.51, 95% CI 0.3-0.85, p 0.009). Results were consistent when r/r MDS/CMML and HMA-naïve MDS/CMML were analyzed separately. Landmark OS analysis also favored those who received guadecitabine for at least 4 or 6 cycles compared to those who received <4 and < 6 cycles even in the absence of objective response (OS HR of 0.82 and 0.42 respectively) but the sample size was small to show statistical significance (p 0.58 and 0.10 respectively) Summary/Conclusions: In a prospective phase 2 study of 102 MDS/CMML patients treated with the HMA guadecitabine, patients who were alive at the planned start of cycle 4 and cycle 6 did not continue treatment primarily because of patient or investigator decision in addition to early progression. Those who were alive and continued treatment for at least 4 or 6 cycles achieved highly significant objective response benefit compared to those who did not. Survival benefit was highly significant for those who received at least 6 cycles and was not restricted to patients who had an objective response. It is important to weigh reasons for treatment discontinuation carefully before discontinuing guadecitabine HMA treatment in MDS/CMML patients before 6 cycles to maximize response and survival benefit. Disclosures Savona: Selvita: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Takeda: Honoraria; Astex: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Connell:Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Yee:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Research Funding; Hoffman La Roche: Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stock:Research to Practice: Honoraria; UpToDate: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Griffiths:Appelis Pharmaceuticals: Other: PI on a clinical trial; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy; New Link Genetics: Consultancy; Persimmune: Consultancy; Boston Scientific: Consultancy; Genentech, Inc.: Research Funding; Genentech, Inc.: Research Funding; Boston Scientific: Consultancy; Persimmune: Consultancy; Onconova Therapeutics: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Celgene, Inc: Consultancy, Research Funding; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy; Partner Therapeutics: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Podoltsev:Boehringer Ingelheim: Research Funding; Genentech: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Research Funding; Astellas Pharma: Research Funding; Samus Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Celgene: Other: Grant funding, Research Funding; Arog Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AI Therapeutics: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding. Su:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Garcia-Manero:AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; Amphivena: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.

Abstract Background: Guadecitabine SC (SGI-110) is a dinucleotide next generation HMA resistant to degradation by cytidine deaminase resulting in extended in vivo exposure to its active metabolite decitabine. A Phase 1 established 60 mg/m2 QDx5 as the biologically effective dose (BED), and 90 mg/m2 QDx5 as the Maximum tolerated dose (MTD) in MDS patients given in 28-day cycles (Issa et al, 2015, Lancet Oncology). Phase 2 is conducted to evaluate dose response between the BED and MTD in both untreated MDS patients, and patients previously treated with other HMAs. M ethods: Int, or HR MDS, and CMML patients who were either treatment-naïve (TN) or relapsed/refractory to other HMAs (r/r) were randomized to either 60 mg/m2 or 90 mg/m2 QDx5 every 28 days. Efficacy was evaluated by the clinical responses of CR, PR, marrow CR (mCR), and Hematological Improvement (HI) based on the International Working Group Criteria 2006, as well as transfusion-independence, and overall survival (OS). Adverse events (AEs) were graded by the CTCAE v4 criteria. Results: The study completed target enrolment with 102 patients: 53 r/r MDS, and 49 TN MDS. Fifty three patients were randomized to 60 mg/m2 and 49 patients to 90 mg/m2 QDx5 with a median follow up of 3.2 years (IQR 2.8-3.5 years). Median age was 72 and 71 years for r/r and TN MDS respectively. Most baseline patient characteristics were well balanced between the 2 treatment dose groups except that more CMML patients were randomized to the 60 mg/m2 group (28%) vs. 14% in the 90 mg/m2 group, and more patients with baseline BM blasts >5% were in the 90 mg/m2 group (67%) vs. 38% in the 60 mg/m2 group. Most patients were RBC transfusion-dependent at baseline (57%). In the r/r MDS cohort, most patients (58%) received their last HMA treatment <3 month before enrolment, and most of them received ≥6 months of prior HMA treatment (77%). Median number of treatment cycles was 5 for both r/r and TN MDS (range 1-37 in r/r MDS and 1-49 in TN MDS). In the TN MDS cohort CR was achieved in 11 (22%) of patients with no major difference between the 2 dose groups (19% in the 60 mg/m2 group vs 27% in the 90 mg/m2 group). Overall CR+mCR was achieved in 18 patients (37%) in TN MDS patients and median OS was 23.4 months. In the r/r MDS cohort, CR was achieved in 4% of patients in each of the 2 dose groups. Overall CR+mCR in the r/r MDS cohort was achieved in 17 patients (32%), with a median duration of response of 7.9 months, and median OS of 11.7 months. No significant difference in response or OS between the 2 dose groups was observed. In patients who were RBC transfusion-dependent at baseline, transfusion independence for at least 8 weeks was achieved in 42% of TN MDS, and 15% in r/r MDS patients. In the overall population of 102 TN and r/r MDS patients there were no major differences in OS based on DNMT3A or TET2 mutation status while patients with TP53 mutations had worse median OS (7.4 months) compared to those without TP53 mutations (22.6 months). Other baseline prognostic factors for worse OS were BM blasts >5%; RBC transfusion-dependence; IPSS High Risk; and ECOG Performance Status of >1. Overall incidence of Grade ≥3 AEs regardless of relationship to treatment was reported in 83 vs. 96% for 60 and 90 mg/m2 dose groups respectively. There was a slightly higher but non-significant difference in Grade ≥3 thrombocytopenia (57 vs 41.5%); neutropenia (51 vs 39.6%); febrile neutropenia (43% vs 32%); and pneumonia (32.7 vs. 26.4%) for the 90 mg/m2 compared to 60 mg/m2 dose group. Early 30, 60, and 90-day all-cause mortality was observed in 0, 3.7%, and 5.7% in the 60 mg/m2 dose group respectively; and in 2%, 4%, and 12% in the 90 mg/m2 dose group respectively. Conclusions: Guadecitabine at both dose groups is a well-tolerated novel HMA with clinical activity in the treatment of both TN and r/r Int and HR MDS, and CMML patients. In TN MDS patient CR rate of 22% and median OS of 23.4 months compare well with first generation HMA efficacy (Fenaux et al, 2009, Lancet Oncology). Activity in r/r MDS who previously failed prior HMAs is particularly promising (CR+mCR in 32% of patients with median duration of response and overall survival of almost 8 and 12 months respectively). A phase 3 trial (ASTRAL-3) of guadecitabine vs Physician Treatment Choice in r/r MDS and CMML patients previously treated with azacitidine or decitabine is actively enrolling (ClinicalTrials.gov ID: NCT02907359). Disclosures Ritchie: NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kropf:Celegene: Consultancy; Takeda: Consultancy. Daver:Pfizer: Consultancy; Sunesis: Consultancy; Pfizer: Research Funding; ImmunoGen: Consultancy; ARIAD: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Otsuka: Consultancy; Novartis: Consultancy; Karyopharm: Consultancy; Alexion: Consultancy; Incyte: Consultancy; Karyopharm: Research Funding; BMS: Research Funding; Kiromic: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Yee:Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees; Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Griffiths:Alexion Inc.: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Celgene, Inc: Honoraria, Research Funding; Novartis, Inc.: Research Funding; Pfizer, Inc.: Research Funding. Podoltsev:Astex Pharmaceuticals: Research Funding; LAM Therapeutics: Research Funding; Sunesis Pharmaceuticals: Research Funding; Genentech: Research Funding; Boehringer Ingelheim: Research Funding; Daiichi Snakyo: Research Funding; Astellas Pharma: Research Funding; Pfizer: Research Funding; Celator: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding. Berdeja:Genentech: Research Funding; Bluebird: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Glenmark: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Teva: Research Funding; Sanofi: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Roboz:Orsenix: Consultancy; Roche/Genentech: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Astex Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Sandoz: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Celgene Corporation: Consultancy; Jazz Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Argenx: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Aphivena Therapeutics: Consultancy; AbbVie: Consultancy; Aphivena Therapeutics: Consultancy; AbbVie: Consultancy; Cellectis: Research Funding.

Abstract Background: SGI-110 is a second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume SC injection that yields longer half-life and more extended DAC exposure than DAC IV infusion. A phase 1 clinical trial of SGI-110 demonstrated a differentiated pharmacokinetic profile from DAC IV, potent hypomethylation, and clinical responses in previously treated patients with MDS and AML (Kantarjian et al. 2012). Phase 1 established 60 mg/m2 QDx5 as the biologically effective dose (BED), and 90 mg/m2QDx5 as the Maximum tolerated dose (MTD) in MDS patients given in 28-day cycles. Phase 2 is conducted to evaluate dose response between the BED and MTD in MDS patients. Methods: Int, or HR MDS, and CMML patients who were either treatment-naïve or previously treated were randomized to either 60 mg/m2 or 90 mg/m2QDx5 every 28 days. Efficacy was evaluated by the clinical responses of CR, PR, marrow CR (mCR), and Hematological Improvement (HI) based on the International Working Group Criteria 2006 as well as transfusion-independence. Adverse events (AEs) as graded by the CTCAE v4 criteria and pharmacodynamic biological activity as measured by Long Interspersed Nucleotide Element LINE-1 (an index of global DNA methylation) were also assessed. Patients are being followed for overall survival. Results: The study completed target enrolment with 102 patients: 53 who were refractory or have relapsed on prior treatment, and 49 previously untreated. Fifty three patients were randomized to 60 mg/m2 and 49 patients to 90 mg/m2 QDx5 with a median follow up of 8.2 months (range 1-21). Most baseline patient characteristics were well balanced between the 2 treatment arms with no significant differences in median age (71.7 vs. 72.5 y); male gender (70 vs. 61%); ECOG PS 2 (15 vs. 12%); HR MDS (28 vs. 37%); transfusion-dependence (57 vs. 55%), median baseline Hb (9.25 vs. 9.3 g/dL); platelets count (42.5 vs. 45 x109/L), and neutrophils count (1.19 vs. 1.16 x109/L) for the 60 and 90 mg/m2 QDx5 respectively. However, there were 15 CMML patients (28%) randomized to 60 mg/m2 vs. only 7 CMML patients (14%) randomized to 90 mg/m2(p=0.097). All but 2 patients in the previously treated group received one or more HMA. At the time of the data cutoff, 38 of 102 patients (37%) were still on treatment. Median number of treatment cycles was 4 for previously treated patients, and 5 for the treatment naïve group (range 1-22 cycles). CR+mCR were observed in 10/53 (19%), and 11/49 (22%) in the 60 and 90 mg/m2 arms respectively (p=0.8). CR was observed in 7/49 treatment naïve patients (14%) while CR+mCR were observed in 11/53 previously treated patients (21%) with no significant differences between 60 and 90 mg/m2 arms. Transfusion independence for at least 8 weeks was reported in 32% and 24% for platelets and RBCs respectively with no difference between the 2 treatment arms. Treatment naïve patients benefited from higher rate of transfusion-independence (58% and 46% for platelets and RBCs respectively). Potent demethylation was achieved in both treatment arms with a mean LINE-1 DNA demethylation of 27.3 and 30.5% for 60 and 90 mg/m2 respectively (p=0.12). Overall incidence of Grade ≥3 AEs regardless of relationship to treatment was reported in 81 vs. 88% for 60 and 90 mg/m2 treatment arms respectively (p=0.42).There was a slightly higher but non-significant difference in Grade ≥3 thrombocytopenia (51 vs 38%) and pneumonia (20 vs. 13%) for the 90 mg/m2 arm compared to 60 mg/m2. Early 8-week any-cause mortality occurred in 3/102 patients treated (3%), 2 at 60 and 1 at 90 mg/m2. Follow up for survival is still ongoing. Conclusions: SC SGI-110 is a well-tolerated novel HMA with biological and clinical activity in the treatment of Int and HR MDS, and CMML patients with particularly promising activity in patients previously treated with azacitidine or decitabine. Clinical responses, transfusion independence, DNA demethylation as assessed by LINE-1, and Safety did not significantly differ between the 2 treatment doses. Disclosures Tibes: Astex Pharmaceuticals, Inc.: Research Funding. Rosenblat:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Issa:Astex Pharmaceuticals, Inc.: Consultancy, Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Roboz:Astex Pharmaceuticals, Inc.: Consultancy.