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BackgroundAcute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML.MethodsThis randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (

Background In neuroblastoma, genetic alterations in ATRX, define a distinct poor outcome patient subgroup. Despite the need for new therapies, there is a lack of available models and a dearth of pre-clinical research. Methods To evaluate the impact of ATRX loss of function (LoF) in neuroblastoma, we utilized CRISPR-Cas9 gene editing to generate neuroblastoma cell lines isogenic for ATRX. We used these and other models to identify therapeutically exploitable synthetic lethal vulnerabilities associated with ATRX LoF. Findings In isogenic cell lines, we found that ATRX inactivation results in increased DNA damage, homologous recombination repair (HRR) defects and impaired replication fork processivity. In keeping with this, high-throughput compound screening showed selective sensitivity in ATRX mutant cells to multiple PARP inhibitors and the ATM inhibitor KU60019. ATRX mutant cells also showed selective sensitivity to the DNA damaging agents, sapacitabine and irinotecan. HRR deficiency was also seen in the ATRX deleted CHLA-90 cell line, and significant sensitivity demonstrated to olaparib/irinotecan combination therapy in all ATRX LoF models. In-vivo sensitivity to olaparib/irinotecan was seen in ATRX mutant but not wild-type xenografts. Finally, sustained responses to olaparib/irinotecan therapy were seen in an ATRX deleted neuroblastoma patient derived xenograft. Interpretation ATRX LoF results in specific DNA damage repair defects that can be therapeutically exploited. In ATRX LoF models, preclinical sensitivity is demonstrated to olaparib and irinotecan, a combination that can be rapidly translated into the clinic. Funding This work was supported by Christopher's Smile, Neuroblastoma UK, Cancer Research UK, and the Royal Marsden Hospital NIHR BRC.

Background DFP-10917, a deoxycytidine nucleoside analogue, has a unique mechanism of action resulting in leukemic cell death when administered for prolonged periods at low doses. The current phase 1/2 study investigated the safety, maximum tolerated dose, and evidence of antileukemic activity for DFP-10917 administered by 7-day or 14-day continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia (AML). Methods In the phase 1 dose escalation portion of the study, patients were administered DFP-10917 by 7-day continuous intravenous infusion plus 21-day rest (stage 1) or 14-day continuous intravenous infusion plus 14-day rest (stage 2). The primary objectives of phase 1 were to determine the maximum tolerated dose, the phase 2 dose, and the dose-limiting toxicities (DLTs) of DFP-10917. The primary objectives of phase 2 were to evaluate the overall response rate of DFP-10917 using complete response (CR), CR without platelet recovery (CRp), CR with incomplete blood count recovery (CRi) or partial response. Results In stage 1 of phase 1 (4-35 mg/m2 /day as a 7-day continuous intravenous infusion), a DLT of grade 3 diarrhea occurred at a dose of 35 mg/m2 /day. In stage 2 of phase 1, a dose of 10 mg/m2 /day as a 14-day continuous intravenous infusion resulted in DLTs of prolonged hypocellularity, abdominal pain, diarrhea, and vomiting. The dose of 6 mg/m2 /day as a 14-day continuous intravenous infusion was found to be well tolerated and was selected for phase 2. Response rates in patients in phase 2 (N = 29) were 20.7% CR, 3.4% CRp, and 24.1% CRi. The overall response rate was 48.3% (95% confidence interval, 29.4%-67.5%). Conclusions DFP-10917 as a 14-day continuous intravenous infusion at a dose of 6 mg/m2 /day can be administered safely and appears to be effective in patients with recurrent or refractory AML. A phase 3 investigation comparing DFP-10917 monotherapy versus standard of care in an early recurrent or refractory AML setting is warranted.

Background: Sapacitabine is a novel, orally bioavailable, cytosine nucleoside analogue with a unique mechanism that generates single-stranded DNA breaks which are converted into double-stranded DNA breaks resulting in cell death. Previous studies of sapacitabine alone and alternating with decitabine (DAC) have demonstrated activity in acute myeloid leukemia (AML). Preclinical studies have suggested synergy with the combination of sapacitabine and a BCL-2 inhibitor. We conducted a study investigating the combination of sapacitabine and venetoclax (VEN) as an entirely oral regimen for patients with relapsed/refractory (R/R) AML. Methods: This is a phase I/II study for patients ≥ 18 years with R/R AML or MDS with blasts ≥10% investigating the safety and efficacy of escalating doses of sapacitabine combined with VEN. Eligibility included ECOG performance status ≤ 2 and adequate organ function. Two cohorts were investigated: Cohort 1 studied sapacitabine given PO BID on D1-5; Cohort 2 studied sapacitabine given PO BID on D1-3 and D8-10 of each cycle, which was defined as 4 weeks. Sapacitabine was escalated from a starting dose of 250mg. VEN was given to a target dose of 400mg PO on D1-14 of each cycle. VEN ramp-up was utilized, starting at 100mg on D1, 200mg on D2, and 400mg on days 3 through 14. Adjustments to the VEN dose were made based on concomitant CYP3A inhibitors. Results: Between 03/2020 and 03/2021, 13 pts were enrolled in the study. Baseline characteristics are shown in table 1. The median age was 70 years (range, 30-82) and 8 pts (62%) were aged ≥ 70 years. One pt (7%%) had favorable risk, 3 (23%) had intermediate risk, and 9 (70%) had adverse risk karyotype; 5 pts (38%) had a complex karyotype. The most common mutations detected by next-generation sequencing were: TET2 (46%), ASXL1 (30%), NRAS (30%), and WT1 (23%%). One patient (8%) had a TP53 mutation. This was a heavily pretreated population, having received a median of 2 prior therapies (1 - 9), including 6 patients (46%) having received prior intensive chemotherapy and 4 patients (30%) with prior allogeneic SCT. Six patients (46%) had received prior VEN-based therapy. Among 13 evaluable patients, there was 1 (8%) complete response with incomplete platelet recovery (CRp). Patients received a median of 1 cycle (1-9) on protocol. Five patients (38%) were able to remain on protocol without a protocol defined response, but with clinical benefit and good tolerability, for ≥2 cycles. With a median follow up of 14.61 months (1-16), the median overall survival (OS) was 3.8 months with a 60-day survival rate of 76% (Figure 1). There was no significant difference in OS between the two dosing schedules. The median OS among patients that had and had not received prior VEN was 3.32 months and 4.5 months, respectively (P=0.25). The patient that achieved a CRi had secondary AML with 7q deletion, an ASXL1 mutation, and only single-agent DAC as prior therapy. The oral chemotherapy combination was well tolerated, with 4- and 8-week mortality of 8% and 15%, respectively. The most common grade 3/4 non-hematologic adverse events regardless of attribution were: febrile neutropenia (31%), cellulitis (23%) pneumonia (15%), hypophosphatemia (8%), hypokalemia (8%). Two patients (15%) had grade 5 sepsis on study in the setting of active AML. Conclusion: In a heavily pretreated population of patients with R/R AML, the combination of sapacitabine and VEN was well tolerated and feasible to be administered as a completely oral, outpatient regimen. Most patients had multiple prior cycles of nucleoside analogue containing regimens and the only notable responder had only prior DAC. Further study of this well-tolerated combination in less heavily pretreated patients may be considered. Figure 1 Figure 1. Disclosures Kantarjian: Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Aptitude Health: Honoraria; NOVA Research: Honoraria; Ascentage: Research Funding; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. DiNardo: Novartis: Honoraria; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Borthakur: GSK: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Protagonist: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Ryvu: Research Funding. Daver: ImmunoGen: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Hanmi: Research Funding; Sevier: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Pemmaraju: Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Daiichi Sankyo, Inc.: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; Roche Diagnostics: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; MustangBio: Consultancy, Other; Cellectis S.A. ADR: Other, Research Funding; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CareDx, Inc.: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Alvarado: Sun Pharma: Consultancy, Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding. Burger: AstraZeneca: Consultancy; Beigene: Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Ravandi: Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding. Kadia: AstraZeneca: Other; Ascentage: Other; Jazz: Consultancy; BMS: Other: Grant/research support; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Amgen: Other: Grant/research support; Cure: Speakers Bureau; Dalichi Sankyo: Consultancy; Genfleet: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Novartis: Consultancy; Pfizer: Consultancy, Other; Liberum: Consultancy; Genentech: Consultancy, Other: Grant/research support; Astellas: Other.

INTRODUCTION Acute myeloid leukemia (AML) remains a poor prognosis hematological malignancy. The introduction of aggressive chemotherapy with allogeneic stem cell transplantation has resulted in improved clinical outcomes in younger patients. However, the treatment results in unfit elderly AML population remain disappointing. New strategies should be introduced to improve the prognosis in this group of patients. Areas covered: This review presents and discusses the mechanism of action, safety and efficacy of sapacitabine in AML patients. Expert opinion: Sapacitabine, a novel nucleoside analog, seemed to be a promising new agent for AML treatment. Its oral bioavailability and tolerable toxicity profile allow the drug to be used in an outpatient setting, especially in elderly unfit patients. Sapacitabine is known to have antileukemic activity in randomized clinical trials. In AML patients, sapacitabine monotherapy offered no advantage over low-intensity cytarabine treatment, and the combination of sapacitabine with decitabine was not significantly more effective than decitabine alone. However, the oral administration of sapacitabine allows it to be used in AML maintenance therapy.

Introduction: The treatment of acute myelogenous leukemia remains challenging, especially in older adults or those unfit for intensive induction therapy or allogeneic stem cell transplant. Sapacitabine is a novel, rationally-designed, orally administered nucleoside analog that has shown promising activity in early clinical trials in acute myelogenous leukemia. Areas covered: This review covers the biochemical and pharmacologic properties of the drug with a focus on the clinical activity, safety and tolerability of sapacitabine in the treatment of acute myelogenous leukemia. Expert opinion: Sapacitabine is a promising orally administered drug in the treatment of acute myelogenous leukemia. While clinical data have failed to show significant benefit as a single agent, the drug has demonstrated clinical activity as monotherapy. Early clinical data has shown encouraging results in combinations with other agents.

The development of new treatments for older patients with acute myeloid leukaemia (AML) is an active area, but has met with limited success. Sapacitabine is a novel orally administered nucleoside analogue that has shown encouraging activity in unrandomised early-stage trials. We randomised 143 untreated patients with AML or with high-risk myelodysplastic syndrome (>10% marrow blasts) between sapacitibine and low-dose ara-C (LDAC) in our ‘Pick a Winner’ trial design. At the planned interim analysis there was no difference between LDAC and sapacitibine in terms of remission rate (CR/CRi, 27% vs 16% hazard ratio (HR) 1.98(0.90–4.39) P=0.09), relapse-free survival (10% vs 14% at 2 years, HR 0.73(0.33–1.61) P=0.4) or overall survival (OS; 12% vs 11% at 2 years, HR 1.24(0.86–1.78) P=0.2). Sapacitibine was well tolerated, apart from more grade 3/4 diarrhoea. On the basis of these findings sapacitibine did not show sufficient evidence of benefit over LDAC for the trial to be continued.

Acute myeloid leukemia (AML) is characterized by clonal proliferation of neoplastic myeloid precursor cells resulting in impaired hematopoiesis. Despite initial responses to intensive induction therapy, relapses are frequent and most patients die in less than 5 years (National Cancer Institute 2015). Nucleoside analogues represent an important category of anti-leukemic cytotoxic drugs. Cytarabine (Ara-C) is the most active drug against AML; azacitidine and decitabine are active treatments of myelodysplastic syndrome (MDS) and AML. Sapacitabine is a novel, orally bioavailable nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading eventually to production of double-strand DNA breaks and/or G2 cell cycle arrest. In phase 1 and 2 clinical trials, sapacitabine has induced complete remission (CR), CR with incomplete platelet count recovery (CRp), partial remission (PR), and major hematological improvement (HI) in patients with AML and MDS. A subset of these responding patients were previously treated with other nucleoside analogues, suggesting that the anti-leukemic activity of sapacitabine is not limited by resistance to other nucleoside analogues (Kantarjian H et al, JCO, 2010, ASH, 2013). Two clinical studies have demonstrated the synergistic activity of venetoclax in combination with hypomethylating agents or low-dose ara-C in newly diagnosed AML, leading to its recent approval by the FDA for the front-line treatment of this disease. The synergy between venetoclax and cytotoxic therapy in AML models is mediated by combined targeting of the anti-apoptotic BCL2 and MCL1 mechanisms (Teh T-C et al, Leukemia, 2018). Cytotoxic drugs induce apoptosis through genotoxic damage, TP53 activation and increased expression of pro-apoptotic NOXA and PUMA (Villunger A et al, Science, 2003) - features that have also been demonstrated for sapacitabine (Green S et al. Br J Cancer 2010). Although most cytotoxic agents do not directly affect MCL1 levels, increased levels of the pro-apoptotic NOXA and PUMA proteins can inactivate MCL1 to synergize with venetoclax to induce apoptosis. The combination of CNDAC (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentafuranosylcytosine), the active metabolite of sapacitabine, and BCL2 inhibitor ABT737 was studied in AML cell line MV-411. A synergistic increase in apoptosis induction was observed when CNDAC and ABT737 were combined (Frame S. et al, 14th EHA, 2009, Abs 0761). The above findings support the conduct of a clinical study (NCT01211457) evaluating a combination of sapacitabine with venetoclax in patients with relapsed/refractory AML and MDS. This is an entirely oral treatment regimen. The primary objective is to evaluate the safety and efficacy of two dosing schedules of sapacitabine given concomitantly with venetoclax: twice daily for 5 consecutive days or twice daily for 3 consecutive days per week for 2 weeks. One treatment cycle is 4 weeks. Dose will be escalated in increments of 50 mg twice daily. RP2D is the highest dose level at which ≤2 of 6 patients experience a dose-limiting toxicity during the first 2 treatment cycles. Eligible patients are ≥18 years with previously treated AML or MDS and ≥10% blasts in bone marrow or peripheral blood; adequate bone marrow, renal and liver functions are required. Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment. Laboratory tests and bone marrow aspirate/biopsy will be performed to assess responses according to standard criteria. Disclosures Kadia: Bioline RX: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Borthakur:Agensys: Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding; Janssen: Research Funding; Merck: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; Novartis: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Arvinas: Research Funding; AbbVie: Research Funding; Incyte: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy. Jabbour:Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Konopleva:Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo:celgene: Consultancy, Honoraria; medimmune: Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Zheleva:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Blake:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Chiao:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties.

Introduction: Sapacitabine, a nucleoside analog, and seliciclib, a cyclin-dependent kinase 2/9 inhibitor, constitute a novel oral regimen aimed at augmenting DNA damage and impairing cell cycle checkpoints. The initial phase I cohort investigating this combination demonstrated a 25% response rate in BRCA carriers. Hence, we developed an expansion cohort to assess the safety and efficacy of this regimen in patients with metastatic breast cancer and BRCA1/2 mutations. Methods: We enrolled 20 patients with HER2-negative metastatic breast cancer and germline or somatic BRCA1/2 mutations, who were treated with sapacitabine 50 mg twice daily for days 1-7 followed by seliciclib 800 mg twice daily for days 8-10 of a 21-day cycle. Baseline or archival biopsies underwent RAD51 immunohistochemistry to assess for functional homologous recombination proficiency. Available tissue was sent for whole exome and transcriptome sequencing, and pre- and post-treatment blood was submitted for cell-free DNA sequencing to assess for genomic correlates of response. Results: Participants received a median of 2 prior lines of chemotherapy for metastatic disease. Of the 9 patients who received a prior platinum agent, 6 progressed on this therapy. In addition to chemotherapy, 7 patients received and progressed on a prior PARP inhibitor. The overall response rate for sapacitabine and seliciclib in this cohort was 10%, consisting of 2 patients with partial responses lasting 4.7 and 9.0 months, respectively. The clinical benefit rate (CR + PR + SD ≥ 6 months) was 30%, and durations of stable disease ≥ 6 months ranged from 7.4 to 11.7 months. For all patients, median PFS was 3.7 months. The most frequent grade 3/4 adverse events were neutropenia (25% of patients), transaminitis (20%), and rash (10%). No patients who progressed on prior PARP inhibitor therapy and 6 of 13 patients (46%) with no history of PARP inhibitor resistance experienced clinical benefit (p = 0.052 by Fisher’s exact test). In contrast, 1 of 6 patients (17%) who progressed on prior platinum chemotherapy and 5 of 14 patients (36%) with no history of platinum resistance experienced clinical benefit (p = 0.61 by Fisher’s exact test). Notably, the tumors of some resistant patients harbored BRCA reversion mutations. Additional genomic analyses and RAD51 immunohistochemistry will be presented. Conclusions: The combination of sapacitabine and seliciclib was safe and led to durable clinical benefit in some patients with metastatic breast cancer and BRCA1/2 mutations. Prior progression on PARP inhibitors predicted resistance to this combination, associated in some cases with BRCA reversion mutations. Based on these results, the combination of sapacitabine and the PARP inhibitor olaparib is now being investigated in patients with PARP-naïve metastatic HER2-negative breast cancer and germline BRCA1/2 mutations. Citation Format: Tanya Keenan, David Liu, Haitham Elmarakeby, Daniel Stover, Bose Kochupurakkal, Adam Tracy, Elaine Danielczyk, Leilani Anderson, Chelsea Andrews, Brendan Reardon, Beth Overmoyer, Eric Winer, Daniella Zheleva, Judy Chiao, David Blake, Eliezer Van Allen, Geoffrey I. Shapiro, Sara Tolaney. Expansion cohort of Phase I study of oral sapacitabine and oral seliciclib in patients with metastatic breast cancer and BRCA1/2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT050.

Therapies for AML have remained mostly unchanged since the introduction of anthracyline- and cytarabine-based regimens in the 1970s. Though some changes have been made in the dosing of anthracylines, in the choice of consolidation regimens versus allogeneic stem cell transplant, and in supportive care, clinical outcomes remain poor for most patients. As we continue to strive for better treatment options to improve upon outcomes, different agents, both chemotherapeutic and targeted therapies, are being studied. Here we discuss new chemotherapeutic agents that show promise in recent clinical trials and attempt to answer the question if there are any new effective cytotoxic chemotherapy agents out there.

Summary Background Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. Methods In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20–25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. Results Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16–59) in group A, 10% (2–33) in group B, and 30% (13–54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3–4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. Interpretation Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. Funding Cyclacel Limited.

PURPOSE OF REVIEW Nucleoside analogs remain a cornerstone in acute myeloid leukemia therapy. As many new nucleosides are being investigated in clinical trials, this review aims to update the current state of experience with these new compounds and where they may fit into treatment strategies for acute myeloid leukemia. RECENT FINDINGS Many new nucleoside analogs are emerging with novel metabolic properties and mechanisms of action. Some have entered clinical trials and are actively investigated in the context of acute myeloid leukemia therapy. Clofarabine is the most-developed compound, and single-agent experience and combinations with other active agents in acute myeloid leukemia are being explored. Troxacitabine and sapacitabine are still in single-agent phases of their development and clinical experience is accumulating quickly. SUMMARY Nucleosides remain the most important class of drugs in acute myeloid leukemia and the interest in new compounds is strong. The plethora of new analogs continues to provide ample opportunity to expand the effectiveness of these drugs in acute myeloid leukemia therapy. Furthermore, their unique mechanisms of action provide possibilities for mechanism-based combinations.

BackgroundCancer control by radiotherapy (RT) can be improved with concurrent chemotherapy. Outpatient strategies for sarcomas that combine chemotherapy and RT are possible since supportive care and RT techniques have improved.MethodsThe current status of non-anthracycline chemotherapy in combination with radiation for high-risk sarcoma is reviewed.ResultsIfosfamide with mesna and newer activated ifosfamide agents (ZIO-201 and glufosfamide) have high potential to improve sarcoma cancer control. In Ewing's sarcoma and osteosarcoma, high-dose ifosfamide with mesna (2.8 g/m2/day of each x 5 days; mesna day 6) can be safely given to outpatients using continuous infusion. Reducing ifosfamide nephrotoxicity and central nervous system side effects are discussed. Other outpatient radiosensitization regimens include gemcitabine (600–1000 mg/m2/dose IV over 1 hour weekly x 2–3 doses), temozolomide (75 mg/m2/daily x 3–6 weeks), or temozolomide (100 mg/m2/dose daily x 5) + irinotecan (10 mg/m2/dose daily x 5 x 2 weeks). In osteosarcoma with osteoblastic metastases on bone scan, samarium (1 mCi/kg; day 3 of RT) and gemcitabine (600 mg/m2IV over 1 hour day 9 of RT) is a radiosensitization strategy. Future drugs for radiosensitization include beta-D-glucose targeted activated ifosfamide (glufosfamide) and sapacitabine, an oral nucleoside with in vitro activity against solid tumors including sarcomas.ConclusionsThe potential to treat major causes of sarcoma treatment failure (local recurrence and distant metastases) with concurrent chemotherapy during radiation should be considered in high-grade sarcomas.

More than half of the patients with acute myeloid leukaemia (AML) are older than 60years. The treatment outcomes in this group remain poor with a median overall survival of

Prognosis of elderly patients with acute myeloid leukemia (AML) remains poor and new treatment approaches are urgently needed. A novel nucleoside analog sapacitabine has recently emerged as a feasible agent because of its oral administration and acceptable toxicity profile. Clinical efficacy of sapacitabine, both as a single agent and in combination, has been evaluated in elderly AML patients or AML patients unfit for standard intensive chemotherapy. Response rates varied from 15 to 45% in phase II studies. Sapacitabine was overall well-tolerated with gastrointestinal and myelosuppression-related complications were the most common side effects. Unfortunately, in a phase III study sapacitabine showed no clinical superiority as compared to low-dose cytarabine (LDAC) in patients with AML. Another large phase III study comparing the combination of sapacitabine with decitabine to decitabine alone is currently ongoing and is expected to be completed by the end of 2015 or by the first half of 2016.

Background: Sapacitabine is a novel oral nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading to production of double-strand DNA breaks and/or G2 cell cycle arrest. In AML cell lines, the active metabolite of sapacitabine, CNDAC, is synergistic with hypomethylating agents (HMAs) particularly when treated with HMAs first. In a pilot study, there were 6 CRs and 2 PRs in 25 patients treated with sapacitabine in alternating cycles with decitabine. This global randomized phase 3 study evaluated the survival benefit of this treatment strategy vs. decitabine monotherapy. Methods: Decitabine 20 mg/m2 was administered intravenously daily x 5 days of a 4-week cycle (for the control arm and odd cycles of the study arm) alternating with sapacitabine 300 mg p.o. b.i.d. x 3 days/week x 2 weeks of a 4-week cycle (even cycles of the study arm). The safety of these doses was further evaluated in the lead-in phase of the phase 3 study to confirm the findings from the pilot study. Eligible patients were ≥70 years with untreated AML and unsuitable for or unwilling to receive standard induction chemotherapy. Patients who had received HMAs for prior MDS or MPD were excluded. Results: For 482 patients randomized to receive decitabine/sapacitabine (n=241) vs. decitabine only (n=241), randomization was stratified by the presence of antecedent MDS or MPN, peripheral white blood cell count (WBC 40,000 in 59 patients (12%); 194 patients (40%) had unfavorable cytogenetic risk by SWOG criteria. Disease characteristics were well balanced in both arms. In total, 13.7% of patients achieved CR, more on the study arm vs. control (16.6% vs. 10.8%). A total of 37.3% treated patients received ≥5 cycles of treatment, similar on both arms, as were 30- and 60-day death rates. Median overall survival was 5.9 months on the study arm vs. 5.7 months on control arm, which did not reach a statistically significant difference. In the subgroup of patients with 10% patients were thrombocytopenia, anemia, neutropenia, pneumonia, febrile neutropenia, sepsis, and disease progression. Conclusion: The regimen of sapacitabine administered in alternating cycles with decitabine was active and well tolerated but it did not significantly improve overall survival as compared to decitabine monotherapy. Further analyses are being conducted to characterize the subgroups of patients who appeared to have benefited from this treatment regimen and the potential cost savings associated with the use of an oral drug. Disclosures Kantarjian: Amgen: Research Funding; Pfizer: Research Funding; Delta-Fly Pharma: Research Funding; ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Novartis: Research Funding. Goldberg: Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; COTA: Employment, Equity Ownership; Pfizer: Honoraria; Ariad: Speakers Bureau; Jazz: Speakers Bureau. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Strickland: Boehringer Ingelheim: Consultancy; Daiichi Sankyo: Consultancy; CTI BioPharma: Consultancy; Tolero Pharmaceuticals: Consultancy; Sunesis Pharamaceuticals: Consultancy, Research Funding; Baxalta: Consultancy; Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Honoraria. Rubenstein: Alexion Pharmaceuticals: Speakers Bureau. Arellano: Cephalon Oncology: Research Funding. Schiller: bluebird bio: Research Funding; mateon therapeutics: Research Funding. Gaidano: Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Montesinos: Celgene Corporation: Honoraria, Research Funding. Rizzieri: Shire: Research Funding; Erytech: Research Funding. Subramanian: Boehringer-Ingelheim, Lilly, BMS, Astra-Zeneca, Pfizer, Biocept: Consultancy, Speakers Bureau. Buyse: IDDI: Employment, Equity Ownership. Chiao: Cyclacel LTD: Employment, Equity Ownership.

Acute myeloid leukemia (AML) is the second most common form of leukemia and the most frequent cause of leukemia-related deaths in the United States. The incidence of AML increases with advancing age and the prognosis for patients with AML worsens substantially with increasing age. Many older patients are ineligible for intensive treatment and require other therapeutic approaches to optimize clinical outcome. To address this treatment gap, novel agents with varying mechanisms of action targeting different cellular processes are currently in development. Hypomethylating agents (azacitidine, decitabine, SGI-110), histone deacetylase inhibitors (vorinostat, pracinostat, panobinostat), FMS-like tyrosine kinase receptor-3 inhibitors (quizartinib, sorafenib, midostaurin, crenolanib), cytotoxic agents (clofarabine, sapacitabine, vosaroxin), cell cycle inhibitors (barasertib, volasertib, rigosertib) and monoclonal antibodies (gentuzumab ozogamicin, lintuzumab-Ac225) represent some of these promising new treatments. This review provides an overview of novel agents that have either completed or are currently in ongoing phase III trials in patients with previously untreated AML for whom intensive treatment is not an option. Other potential drugs in earlier stages of development will also be addressed in this review.

High-risk acute myeloid leukemia (AML) is defined by clinical and biologic features that predict for poor response to induction chemotherapy and high risk of relapse. Despite even the most aggressive and well-developed strategies for care, most patients succumb to the disease. No currently available treatment has demonstrated consistent efficacy in terms of remission induction or long-term survival. This review will highlight some of the emerging strategies to treat high-risk AML with an emphasis on clinical trials of novel strategies currently enrolling patients. Targeted molecular therapies, novel cytotoxics, and immune-based therapies are under investigation for the management of high-risk AML. Some of the agents covered include tyrosine kinase inhibitors targeted to AML specific oncoproteins, nanoparticle formulations of existing drugs, nucleoside analogs, monoclonal antibodies, chimeric antigen receptors, bispecific T-cell engaging antibodies, and vaccines. As our understanding of the biology of AML has improved, targeted therapy for AML has emerged, offering to change not only response rate, but also the nature of response. Differentiation, rather than necrosis or apoptosis, is often seen in response to targeted agents and may be seen more frequently in the future. Interventions that might be more widely used in the near future include FLT3 inhibitors and nanoparticle formulations of drugs already known to have activity in the disease. Long term immune therapy holds significant promise.

A number of new agents in acute myeloid leukemia (AML) have held much promise in recent years, but most have failed to change the therapeutic landscape. Indeed, with the exception of gemtuzumab ozogamicin (which was subsequently voluntarily withdrawn from the commercial market), no new agent has been approved for acute myeloid leukemia (AML) beyond the 7 + 3 regimen, which was has been in use for over 40 years. This review touches upon the potential reasons for these failures and explores the newer therapeutic approaches being pursued in AML.

2503Background: Sapacitabine is an oral nucleoside analogue; the active metabolite CNDAC generates ssDNA breaks that are converted to dsDNA breaks (DSB) during subsequent replication, resulting in cell death. CNDAC-induced DSB repair is dependent on homologous recombination (HR). Seliciclib is an oral CDK2, 7 and 9 inhibitor, and sensitizes cells to CNDAC by decreasing DSB repair via compromise of HR protein activation. This phase I study evaluates sequential and concomitant sapacitabine and seliciclib treatment. Methods: Dose escalation was conducted in patients with incurable solid tumors with sapacitabine b.i.d. x 7 consecutive days (d 1-7) followed by seliciclib b.i.d. x 3 consecutive days (d 8-10) or sapacitabine q.d. concomitantly with seliciclib q.d. x 5 days per week x 2 weeks (d 1-5, 8-12). MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine and seliciclib treatment. Res...

At present, available therapies are only partially effective in patients with leukemia and the vast majority of patients cannot be cured with current treatment strategies. Hence, there is an obvious need to develop more specific and effective drugs for the treatment of these diseases. In the last twenty years, significant progress in molecular and cellular biology has resulted in a better characterization and understanding of the molecular abnormalities in acute and chronic leukemia. These achievements have provided new opportunities for the development of innovative drugs, and leukemia mortality rates have begun to decline. Molecular-targeted drugs were first introduced for the treatment of hematological malignancies. Imatinib was the first small moleculetargeted drug successfully used for the treatment of chronic myeloid leukemia (CML), and rituximab was the first tumor-specific antibody to be introduced for the treatment of CD20-positive lymphomas and chronic lymphocytic leukemia (CLL). The introduction of imatinib and rituximab has changed the mortality rates associated with CML and B-cell lymphoid malignancies. In CML the availability of tyrosine kinase inhibitors (TKIs) changed the management and prognosis of this disease [1]. However, about 20% of CML patients do not achieve optimal response on imatinib treatment and they need alternative drugs. The availability of second generation TKIs, such as dasatinib and nilotinib, has provided new therapeutic hope for patients with imatinib resistance [2]. In addition, new molecules with different modes of action have demonstrated activity in patients with highly-resistant mutants such as MK0457 and danusertib, which exhibit inhibitory activity against Aurora kinases [3]. Current therapies are frequently inappropriate and unsuccessful for acute myeloid leukemia (AML), especially for older patients. For these patients, there is an obvious need to develop better strategies and new, more specific and active drugs. The search for new drugs in AML has led to the development of many new antileukemic agents potentially active in this form of leukemia [4]. Novel agents potentially useful in the treatment of patients with AML include monoclonal antibodies, molecular target drugs, newer nucleoside analogs and other drugs. These new agents seem unlikely to be curative when administered as monotherapy. They will rather have to be used in combination with other new agents or with more standard therapy. Nucleoside analogs are clinically important antileukemic drugs which compete with physiologic nucleosides and consequently, interact with a large number of intracellular targets. Recently, three novel nucleoside analogs, clofarabine, troxacitabine and sapacitabine, have been introduced into clinical trials in AML and shown promise. However, phase II and III randomized trials are necessary to verify whether these drugs confer an advantage in the treatment of this disease.

Achieving improvements in survival and reducing relapse remains a challenge in acute myelogenous leukemia (AML) patients. This study evaluated thein vitroefficacy of the active form of novel agent sapacitabine, CNDAC, compared to current chemotherapeutic drugs Ara-C and mitoxantrone using two AML cell lines, HL-60 (promyelocytic) and THP-1 (monocytic), as well as bone marrow (BM) and peripheral blood (PB) cells collected from AML patients. Cell lines were exposed to compound for 3–6 days and primary cells for 4 days. The viability of primary cells was additionally evaluated 3, 7, and 31 days after removal of tested compound to determine the durability of the response. Our studies indicate that CNDAC and mitoxantrone have a greater impact on viability than ara-C in primary AML cells and AML cell lines. CNDAC is more effective at reducing viability and inducing apoptosis than ara-C at equivalent concentrations in the THP-1 cell line, which is defined as displaying resistance to ara-C. As sapacitabine has shownin vivoactivity at clinically achievable doses, future studies are warranted to assess the potential for combining it with ara-C and/or mitoxantrone, with an emphasis on cells and patients insensitive to ara-C treatment.

The incidence of acute myeloid leukemia (AML) increases with age, with a median age at diagnosis of 67 years. Older patients have inferior responses to chemotherapy, including not only lower complete remission rates but also short disease-free survival in those who do achieve complete remission. For older patients with a high likelihood of response to chemotherapy, recent data support dose intensification and strong consideration of allogeneic hematopoietic stem cell transplantation. For those unlikely to benefit from chemotherapy because of disease- and/or patient-related factors, novel agents and approaches are being pursued. Agents currently available or under study include the nucleoside analogs clofarabine and sapacitabine, the demethylating agents decitabine and azacitidine, the immunomodulatory agent lenalidomide, and the farnesyl transferase inhibitor tipifarnib. These agents may be administered in the outpatient setting, thus AML in older patients is increasingly becoming an outpatient diagnosis. Additionally, novel agents may prolong survival without inducing complete remissions, and therefore the goals and end points of therapy are also shifting. AML in older patients is a very active current area of investigation.

In the last few years, several new purine and pyrimidine nucleoside analogs have been synthesized and made available for both preclinical studies and clinical trials.This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity as well as the emerging role of newer purine and pyrimidine nucleoside analogs potentially active in lymphoid and myeloid malignancies. A literature review was conducted from the MEDLINE database PubMed for articles in English. Publications from 2000 to October 2010 were scrutinized. The search terms used were clofarabine, nelarabine, forodesine, 8-chloroadenosine, LMP-420, azacitidine, decitabine, sapacitabine, troxacitabine, thiarabine and zebularine in conjunction with hematologic malignancies, leukemia and lymphoma. Conference proceedings from the previous 5 years of the American Society of Hematology, European Hematology Association, and American Society of Clinical Oncology were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles.Several new nucleoside analogs are currently under investigation in preclinical and clinical studies concerning hematological malignancies. Clofarabine, nelarabine, azacitidine and decitabine have been recently approved for the treatment of leukemias and/or myelodysplastic syndromes. Other agents including forodesine, 8-chloroadenosine, LMP-420, sapacitabine, troxacitabine, thiarabine and zebularine seem to be promising for the treatment of lymphoid and myeloid malignancies. However, definitive data from ongoing and future clinical trials will aid in better defining their status in the treatment of hematological disorders.

Prognostic markers, such as NPM1, Flt3-ITD, and cytogenetic abnormalities have made it possible to formulate aggressive treatment plans for unfavorable acute myeloid leukemia (AML). However, the long-term survival of AML with unfavorable factors remains unsatisfactory. The latest data indicate that the standard dose of daunorubicin (DNR) at 45 mg/m2 is inferior to high dose 90 mg/m2 for induction therapy. The rates of complete remission and overall survival are significantly better in the high dose induction regimen. New regimens exploring the new liposomal encapsulation of Ara-C and DNR as well as addition of gemtuzumab ozogamicin monoclonal antibody have been studied. New agents, including the nucleoside analogues (clofarabine, sapacitabine, elacytarabine), FLT3 inhibitor (sorafenib), farnesyl-transferase inhibitor (tipifarnib), histone deacetylase inhibitor (vorinostat), lenalidomide, as well as DNA methyltransferase inhibitors (decitabine, azacitidine), were recently reported for AML treatment in the 2009 ASH annual meeting. This review also summarizes the updates of the clinical trials on novel agents including voreloxin, AS1413, behenoylara-C, ARRY520, ribavirin, AZD1152, AZD6244, and terameprocol (EM-1421) from the 2009 ASH annual meeting.

Purpose Sapacitabine is an oral deoxycytidine nucleoside analog with a unique mechanism of action that is different from cytarabine. Patients and Methods To define the dose-limiting toxicities (DLT) and maximum-tolerated dose (MTD) of sapacitabine given orally twice daily for 7 days every 3 to 4 weeks, or twice daily for 3 days for 2 weeks (days 1 through 3 and days 8 through 10) every 3 to 4 weeks, in refractory-relapse acute leukemia and myelodysplastic syndrome (MDS). A total of 47 patients were treated in the phase I study that used a classical 3 + 3 design. Sapacitabine was escalated from 75 to 375 mg twice daily for 7 days (n = 35) and from 375 to 475 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. Results The DLTs with both schedules were gastrointestinal. The MTDs were 375 mg twice daily for 7 days and 425 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. The recommended phase II single-agent dose schedules were 325 mg twice daily for 7 days and 425 mg twice daily for 3 days on days 1 through 3 and days 8 through 10. Responses were observed in 13 patients (28%); four were complete responses, and nine were marrow complete responses. Conclusion Sapacitabine is a new, safely administered, oral deoxycytidine analog that has encouraging activity in leukemia and MDS. Phase II studies are ongoing.

The development of nucleoside analogues has had a major impact on cancer therapy. CS-682 is a novel, orally administered nucleoside analogue with a unique mechanism of action. CS-682 undergoes conversion to the active metabolite, CNDAC, which then leads to the inhibition of DNA polymerase and a novel "DNA self-strand breaking mechanism." We conducted a Phase I study of CS-682, administered orally five days per week in patients with refractory solid tumor malignancies. Forty-eight patients were enrolled on study. The recommended phase II dose of 30 mg/m(2) given orally once daily for 5 days a week for 4 weeks followed by 2 weeks off drug, was well tolerated. The most common dose limiting toxicity was neutropenia, which occurred at the highest dose levels of CS-682. This was correlated with higher CNDAC Cmax and AUC values. No tumor responses were noted in this heavily pretreated population. However, given the ease of administration and tolerability, further investigation of this agent is warranted.

Acute myeloid leukemia (AML) is a hematopoietic stem cell disorder that affects approximately 14,000 persons each year in the US. AML occurs at all ages but the incidence increases with age with the median age at diagnosis being 67 years. Advances in the treatment of AML over the past decades have led to improved survival, albeit mostly in younger patients. The prognosis of older patients with this disease over the same time span has not changed much and remains dismal. This review focuses on the epidemiology and characteristics of AML in elderly patients, the rationale for treating elderly AML patients, and the currently available and potential future treatment options such as sapacitabine. Elderly AML patients treated with intensive chemotherapy have a higher mortality rate, and a lower rate of complete remission and overall survival when compared to the younger population. This is due to both the different biology of the disease and the number of patient-specific factors. However, elderly AML patients treated with aggressive chemotherapy can achieve durable remissions, which offer prolonged survival and improved quality of life. Recent data also indicates that elderly AML patients deemed unfit for intensive chemotherapy benefit from leukemia-specific attenuated dose chemotherapy compared to supportive care alone. This has led to renewed interest to look for anti-leukemic therapies designed specifically for older patients. Sapacitabine, a novel oral nucleoside analog, promises good efficacy, favorable toxicity profile, and ease of administration; all of which makes it very appealing. Results from pre-clinical and clinical studies have been very encouraging and sapacitabine is currently being evaluated in a Phase III study, of which the results are eagerly awaited.

Background Sapacitabine is an orally administered nucleoside analogue which causes single-strand DNA breaks and induces G2 cell cycle arrest. A multi-center, randomized phase 2 study was conducted to evaluate 3 dose regimens in older patients with MDS refractory to hypomethylating agents. The primary endpoint was 1-year survival. Secondary endpoints included the rate of CR, CRp, PR, major hematological improvement (HI) or stable disease and their corresponding durations. The study used a selection design to identify a dose regimen which produced a better 1-year survival rate in the event that all three dose regimens were active. The planned sample size was 60 patients (20 patients in each arm). Methods Eligible patients were ≥ 60 years with intermediate-2 or higher risk MDS and 6 - < 20% blasts in bone marrow after receiving hypomethylating agents, ECOG 0-2, adequate renal and hepatic functions. Patients were randomized 1:1:1 to receive sapacitabine every 4 weeks at 200 mg b.i.d. x 7 days (Arm G), 300 mg q.d. x 7 days (Arm H), or 100 mg q.d. x 5 days per week x 2 weeks (Arm I). Treatment was continued indefinitely until unacceptable toxicity or disease progression. Results Sixty three patients were randomized and treated (21 patients per arm). Median follow-up was 23.6 months. Median age was 73. Prior therapy also included lenalidomide (n=8), clofarabine (n=1) and fludarabine-based regimen for bone marrow transplant (n=2). Thirteen patients had high risk and all others had intermediate-2 risk. Baseline bone marrow had 10-19% blasts in 40 patients. Median number of cycles was 3 (range: 1- >21) and 30 patients received ≥ 4 cycles. To date, 9 patients have responded (2 CRs, 2 CRp, and 5 major HIs): 19% (Arm G), 10% (Arm H) and 14% (Arm I). Time to response is 1- 3 cycles. Additionally, 21 patients achieved stable disease lasting longer than 16 weeks. Median overall survival was 8.6 months: 9.7 months (Arm G), 9.7 months (Arm H) and 7.6 months (Arm I). One –year survival is 38% (Arm G), 24% (Arm H), and 33% (Arm I). Thirty-day death rate was 5% on each of the arms. Common adverse events regardless of causalities included fatigue, nausea, diarrhea, constipation, pneumonia, edema, pyrexia, epistaxis, febrile neutropenia, anemia, neutropenia and thrombocytopenia, most of which were mild to moderate. Conclusions Sapacitabine appears to be safe and active across all 3 dose regimens. The median survival in all three arms appears to exceed the median survival in published reports of the outcome of MDS patients after treatment failure of hypomethylating agents (Jabbour Cancer 2010, Prebet JCO 2011: median survival 4.3 – 5.6 months). The dose regimen of 200 mg b.i.d. x 7 days (Arm G) has better 1-year survival rate and the highest response rate. Disclosures: Garcia-Manero1: Cyclacel: Research Funding. Wetzler:Cyclacel: data safety monitoring of another study Other, Research Funding. Seiter:Cyclacel: Research Funding. Chiao:Cyclacel: Employment, Equity Ownership, Patents & Royalties. Kantarjian:Cyclacel: Research Funding.

Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite, CNDAC (2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine), generates single-strand DNA breaks that are converted to double-strand DNA breaks (DSBs) during subsequent replication, resulting in cell death if unrepaired. Repair of CNDAC-induced DSBs is dependent on the homologous recombination (HR) repair pathway. Depletion or inhibition of components of the HR pathway (including ATM, BRCA1/2, Rad 51, and XRCC3) greatly sensitizes tumor cell lines to CNDAC-induced cell death in vitro. Seliciclib is an orally bioavailable inhibitor of cyclin-dependent kinases (CDKs) 2, 7 and 9. CDK2 has been shown to participate in DNA repair and to be a therapeutic target in BRCA-deficient cancers. Seliciclib inhibits DSB repair, and also reduces BRCA1 and BRCA2 mRNA levels in cancer cell lines, sensitizing tumor cells to CNDAC. This phase I study evaluates sequential sapacitabine and seliciclib. Methods: Dose escalation was conducted in patients with incurable solid tumors and adequate organ function with sapacitabine bid x 7 consecutive days (d1-7), seliciclib bid x 3 consecutive days (d8-10) followed by 11 days of rest. At least 3 patients were evaluated per dose level. MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine (d8 vs pre-treatment) and further augmentation of DNA damage after seliciclib (d11 vs d8). Results: 38 patients were treated. The MTD is sapacitabine 50 mg bid/seliciclib 1200 mg bid. DLTs were reversible transaminase elevations and neutropenia. The most frequent adverse events (all cycles, regardless of causality) included, fatigue, abdominal pain, diarrhea, constipation, decreased appetite, nausea, vomiting, anemia, neutropenia, pyrexia, AST elevation, alkaline phosphatase elevation, creatinine elevation, hyperglycemia, hypophosphatemia, cough, and alopecia, the majority mild to moderate in intensity. Skin biopsies showed a 2.3-fold increase in γ-H2AX staining post-sapacitabine (n=16; p=0.007) and a further 0.58-fold increase post-seliciclib (n=12; p=0.069). Four confirmed PRs occurred in patients with pancreatic, breast (2 pts) and ovarian cancer, all BRCA mutation carriers, lasting 21, 78+, 36+ and 42+ weeks, respectively. SD as best response ≥= 12 weeks was observed in 8 additional patients, including two BRCA mutation carriers with ovarian and breast cancer, lasting 64 and 21 weeks, respectively. Conclusions: Sequential sapacitabine and seliciclib is safe with preliminary antitumor activity. BRCA mutation carrier status may be a potential biomarker for response across multiple tumor types. An alternative schedule with concomitant administration of sapacitabine and seliciclib is currently under evaluation. Citation Format: Geoffrey I. Shapiro, John Hilton, James M. Cleary, Sara M. Tolaney, Leena Ghandi, Eunice L. Kwak, Jeffrey W. Clark, Andrew Wolanski, Tracy Bell, John Schulz, Sheelagh Frame, Chiara Saladino, Morag Hogben, Scott J. Rodig, Judy H. Chiao, David Blake. Responses to sequential sapacitabine and seliciclib in patients with BRCA-deficient solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-202. doi:10.1158/1538-7445.AM2013-LB-202

3053 Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite CNDAC generates ss DNA breaks that are converted to ds DNA breaks (DSB) during subsequent replication, resulting in cell death if unrepaired. CNDAC-induced DSB repair is dependent on homologous recombination (HR). Seliciclib is a potent orally bioavailable inhibitor of CDK2, 7 and 9, and sensitizes cells to CNDAC by decreasing DSB repair via compromise of HR protein activation and transcriptional inhibition of HR components. This phase I study evaluates sequential sapacitabine and seliciclib. Methods: Dose escalation was conducted in patients with incurable solid tumors and adequate organ function with sapacitabine b.i.d. x 7 consecutive days (d1-7), seliciclib b.i.d. x 3 consecutive days (d8-10) followed by 11 days of rest. At least 3 patients were evaluated per dose level. MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine (d8 vs pre-treatment) and further augmentation of DNA damage after seliciclib (d11 vs d8). Results: 27 patients were treated. The MTD and RP2D is sapacitabine 50 mg b.i.d./seliciclib 1200 mg b.i.d. DLTs were reversible transaminase elevations and neutropenia. The most frequent adverse events (all cycles, regardless of causality) included anorexia, fatigue, abdominal pain, dizziness, nausea, anemia, neutropenia, creatinine elevation, hyperglycemia, hyperbilirubinemia, hypophosphatemia, hypokalemia and hypomagnesemia, the majority mild to moderate in intensity. Skin biopsies showed a 2.3-fold increase in H2AX staining post-sapacitabine (n=16; p=0.007) and a further 0.58-fold increase post-seliciclib (n=12; p=0.069). Two confirmed PRs occurred in patients with pancreatic and breast cancer, both BRCA mutation carriers. SD as best response >/= 12 weeks was observed in 6 additional patients, including one BRCA mutation carrier with ovarian cancer (ongoing at 24 weeks). Conclusions: Sequential sapacitabine and seliciclib is safe with preliminary antitumor activity. BRCA mutation carrier status may be a potential biomarker for response across multiple tumor types.

6520 Background: Sapacitabine is an orally administered nucleoside analogue which causes single-strand DNA breaks and induces G2 cell cycle arrest. A multi-center, randomized phase 2 study was conducted to evaluate 3 dose regimens in older patients with MDS refractory to hypomethylating agents. The primary endpoint is 1-year survival. Secondary endpoints include the rate of CR, CRp, PR, major hematological improvement (HI) or stable disease and their corresponding durations. The study uses a selection design to identify a dose regimen which produces a better 1-year survival rate in the event that all three dose regimens are active. The planned sample size is 60 patients (20 patients in each arm). Methods: Eligible patients must be ≥ 60 years with intermediate-2 or higher risk MDS previously treated with hypomethylating agents and 6 - < 20% blasts in bone marrow, ECOG 0-2, adequate renal and hepatic functions. Patients were randomized 1:1:1 to receive sapacitabine every 4 weeks at 200 mg b.i.d. x 7 days (Arm G), 300 mg q.d. x 7 days (Arm H), or 100 mg q.d. x 5 days per week x 2 weeks (Arm I). The number of cycles is not limited. Results: As of January 2012, 61 patients were enrolled and 56 had ≥ 30 days of follow-up. Mean follow-up was 173 days. Median age was 71. Two or 3 cytopenias were present in 42 patients and 14 have received both azacitidine and decitabine. Baseline bone marrow had 6-10% blasts in 31 patients and 11-19% blasts in 25 patients. Median number of cycles was 2 and 18 patients received ≥ 4 cycles. To date, 8 patients have responded (2 CRs, 2 CRp, and 4 major HIs): 15% (Arm G), 16% (Arm H) and 12% (Arm I). Time to response is 1-3 cycles. Additionally, 6 patients achieved stable disease lasting longer than 16 weeks. More than 50% of patients have lived 16 weeks or longer. Three deaths occurred within 30 days of randomization and 1 death was considered to be related to sapacitabine. Common adverse events (all grades, regardless of causality) included fatigue, nausea, diarrhea, constipation, edema, dyspnea, pyrexia, pneumonia, febrile neutropenia, anemia, neutropenia and thrombocytopenia, most of which were mild to moderate. Conclusions: Sapacitabine appears to be safe and active across all 3 dose regimens. Updated data will be presented at the meeting.

Sapacitabine, a novel, orally available, pro-drug of CNDAC (2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine), is currently being evaluated in SEAMLESS, a pivotal Phase 3 trial in elderly patients with AML, and Phase 2 trials in AML, MDS, NSCLC, and CLL/SLL. CNDAC acts by a unique DNA-damaging mechanism. After CNDAC is incorporated into DNA, single-strand DNA breaks are generated via a β-elimination reaction. If unrepaired, these are subsequently converted to double-strand breaks during further replication. These DNA breaks can also activate the G2 checkpoint, leading to cell cycle arrest in G2. Parallel approaches have been utilized to identify further rational therapeutic development strategies for sapacitabine, particularly focusing on solid tumors. These approaches include synthetic lethality screening using focused siRNA libraries in CNDAC-treated cells, and screening for agents that could synergistically induce cell death when administered in combination with CNDAC. These have demonstrated that depletion or inhibition of components of the homologous recombination DNA repair (HRR) pathway (including ATM, BRCA1/2, Rad 51 and XRCC3) or disruption of the G2 checkpoint greatly sensitizes tumor cell lines to CNDAC-induced cell death. For example, cell lines in which BRCA1 or BRCA2 has been depleted through siRNA are significantly more sensitive to the compound than control cells. Moreover, inhibitors of the ATM or Chk1 kinases also sensitize cells to CNDAC, the latter through abrogation of the G2 checkpoint. These complementary approaches have underscored the potential clinical utility of sapacitabine in patients carrying homologous recombination DNA repair deficient (HRD) tumors, and have also highlighted promising combination strategies. Drug combination screening has also assessed the potential for combining sapacitabine with other agents active in HRD tumors, including platins and PARP inhibitors. Ongoing work is extending these findings to several solid tumor indications, including breast, ovarian and non-small cell lung cancers. Correlation of HRR status and CNDAC sensitivity will be reported for a panel encompassing cell lines derived from each of these target indications, in order to guide future clinical development of sapacitabine in solid tumors, and to aid development of biomarkers to identify suitable patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5666. doi:1538-7445.AM2012-5666

Introduction: Achieving improvements in survival and reducing relapse remains a challenge in acute myelogenous leukemia (AML) patients. This study evaluated the in vitro efficacy of the active form of novel agent sapacitabine, 2′-C-Cyano-2′-deoxy-1-α-d-arabino-pentofuranosylcytosine (CNDAC, Cyclacel Ltd, Dundee, UK), as compared to current chemotherapeutic drugs Ara-C (Cytarabine) and Mitoxantrone (Mit, synthetic anthracenedione) using two AML cell lines, HL-60 (promyelocytic) and THP-1 (monocytic), as well as bone marrow (BM) and peripheral blood (PB) cells collected from 5 AML patients. Methods: Cells lines and AML patient cells were treated in vitro with Ara-C (1-100 µM), CNDAC (1-100 µM) or Mit (0.005-0.5 µM) for 4 days. During treatment, HL-60, THP-1, and PB AML cells were cultured in suspension. BM AML cells were co-cultured with M2-10B4 mouse stromal cells. Cell lines were assessed immediately. BM and PB AML cells were assessed after an additional 3, 7, or 31 days of co-culture on M2-10B4 cells. Treated cells were assessed for sensitivity (cell death by trypan blue and apoptosis by 7AAD/Annexin V) as compared to untreated cells and IC50 values (50% of maximum possible effective response) were calculated. Results: In HL-60 cells, the amount of cell death was greater with CNDAC compared to Ara-C at all doses tested (p≤0.05, n=3). In THP-1 cells, CNDAC and Mit, but not Ara-C, induced a significant apoptotic response. At a 10-fold lower seeding density, which correlates to higher proliferation rates, the response of THP-1 cells to Ara-C, CNDAC and Mit reached significance compared to untreated cells (p≤0.05, n=3). However, the IC50 values for the 3 drugs in THP-1 cells reflect the observation that this cell line is in essence resistant to AraC (IC50 = 7.77 µM) but sensitive to CNDAC (IC50 = 0.929 µM) and Mit (IC50 = 0.003 µM). Using PB AML cells, a significant response to 1 µM CNDAC and 0.005 µM Mit but not 1 µM Ara-C was observed, as compared to untreated cells at all days post drug removal (p≤0.05, n=5). A significantly greater apoptotic response to CNDAC was observed compared to Ara-C at low doses (p≤0.05, n=5). At higher doses, all 3 drugs induced significant cell death (p≤0.05, n=5). In BM AML cells, overall survival with 1 µM CNDAC or 0.005 µM Mit, but not 1 µM Ara-C, was significantly less than untreated cells 31 days post-treatment (p≤0.05, n=5). Higher doses induced cell death (p≤0.05, n=5) with all 3 drugs. Conclusion: Low dose CNDAC and Mitoxantrone induce a greater response than low dose Ara-C in patient AML cells and AML cell lines. CNDAC also exhibits a greater activity in cell lines (THP-1) that are less sensitive to Ara-C. The in vitro sensitivity of AML cells to CNDAC supports the ongoing clinical evaluation of sapacitabine in AML patients. Future studies are warranted to assess the potential for combining sapacitabine with Ara-C and/or Mitoxantrone, with an emphasis on cells and patients insensitive to Ara-C treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4668. doi:1538-7445.AM2012-4668

Abstract 3630 Background: Sapacitabine is a novel nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading to production of double strand DNA breaks and/or G2 cell cycle arrest. It is orally administered and has demonstrated promising activity in patients with acute myeloid leukemia (AML). In AML cell lines, the active metabolite of sapacitabine, CNDAC, is synergistic with hypomethylating agents with the synergy being more apparent if cells are treated with hypomethylating agents first. We are conducting a phase 1/ 2 study to evaluate the safety and efficacy of administering sapacitabine in alternating cycles with decitabine in elderly patients with newly diagnosed AML. Methods: Decitabine 20 mg/m2 was administered intravenously daily × 5 days of a 4-week cycle (odd cycles) alternating with sapacitabine 300 mg po b.i.d. × 3 days/week × 2 weeks of a 4-week cycle (even cycles). After these doses were shown to be safe in the phase 1 part, patients were treated in the Phase 2 part to reach a planned sample size of approximately 24 patients. The primary efficacy endpoint is response rate (CR, CRp, PR, or major HI). The regimen will be considered active if response rate is ≥30%. Eligible patients must be ≥70 years with untreated AML unsuitable for or unwilling to receive standard induction chemotherapy; patients who received hypomethylating agents for prior MDS or MPD are excluded. Results: As of August 2011, 25 patients were treated with the above regimen and 23 had ≥ 60 days of follow-up. Median age is 76 years (range, 72–90). No DLTs were observed. Four patients achieved CR, 3 PR and 2 major HIs in platelets. Median time to response is 2 cycles (range 2– 6). Fifteen patients have received ≥4 cycles of treatment. Three patients died within 60-days and the deaths were unrelated to study drugs by investigator assessment. Common adverse events (regardless of causality) included weakness, anorexia, nausea, constipation, diarrhea, dyspnea, edema, pneumonia, febrile neutropenia, neutropenia, thrombocytopenia, anemia, and hypocalcemia, mostly moderate in intensity. Conclusion: The sequential combination of decitabine and sapacitabine is safe and active in elderly AML. Disclosures: Off Label Use: Decitabine for the treatment of elderly AML. Wetzler:Cyclacel Limited: Research Funding. Chiao:Cyclacel Limited: Employment, Equity Ownership.

Cytogenetic abnormalities are common, and have prognostic implications, in chronic lymphocytic leukemia (CLL). In about 7080% CLL cases, chromosomal abnormalities can be identified by fluorescence in-situ hybridization (FISH) using a disease specific probe set. The most common genomic aberrations include deletion 13q, trisomy 12, and deletion in 11q, 17p and 6q. Approximately 10% of previously untreated patients with CLL exhibit a substantial deletion in the q arm of chromosome 11, the site of the ATM gene at (11q22.3). This lesion occurs at increased incidence of about 40% in patients relapsing on fludarabine-cyclophosphamide-rituximab (FCR) chemoimmunotherapy. The residual ATM allele is often mutated, suggesting that the region containing ATM may be important for response to chemoimmunotherapy. Sapacitabine is the orally bioavailable prodrug of the nucleoside analog CNDAC. It is undergoing clinical trials and has presented favorable clinical activity in advanced acute leukemias and myelodysplastic syndromes. CNDAC induces cell death by a unique mechanism of action. Incorporation of CNDAC triphosphate into DNA results in a single-strand break (SSB), which is converted to a one-ended double-strand break (DSB) upon collapse of the DNA replication fork. We have demonstrated that CNDAC-induced DSBs, which are lethal if not repaired, are repaired predominantly through homologous recombination (HR), relative to other repair pathways, such as transcription-coupled nucleotide excision (TC-NER) and non-homologous end-joining (NHEJ). CNDAC greatly sensitizes the viability of cells lacking HR components, such as ATM, Rad51D, Xrcc3 and Brca2. Based on this evidence, we hypothesize that CLL patients with 11q deletion that lack ATM function will be selectively sensitized to sapacitabinecontaining therapy. In order to distinguish ATM non-functional and functional individuals among del(11q22-23) patients characterized by FISH, we have established an assay of ATM activity. ATM is activated in response to irradiation and will further phosphorylate its downstream targets. We have shown that phosphorylation of KAP1 and Smc1 is dependent on the activity of ATM. In this assay, samples from eight patients with normal FISH karyotype were collected. These samples were mock treated or irradiated at dose of 10 Gy and protein lysates were harvested. The lysates were then combined as a positive pool comparator for the 11q deletion CLL samples, and both total and phosphorylated proteins were quantitated in immunoblots. The averaged phosphorylation level of the KAP1 and Smc1 proteins among the CLL patient samples was calculated and compared with those of the positive pool. The value of the samples to the positive pool of 30% was used as indicative of deficient ATM function. Using this cutoff, we identified five ATM non-functional individuals among ten del(11q22-23) CLL samples isolated from archived stocks. A phase II clinical trial of sapacitabine in combination with cyclophosphamide and rituximab (SCR) for previously treated patients with CLL having del(11q22-23) is open for patient recruitment. We will extend clinical investigations of sapacitabine to these CLL patients, focusing on the comparisons of responses of patients defined by the loss of ATM function. The results will test the hypothesis that loss of ATM function will sensitize the disease to sapacitabine therapy and prevent disease progression.

6587 Background: Sapacitabine is a novel nucleoside analogue with a unique ability to cause irreparable single-strand DNA breaks and induce G2 cell cycle arrest. It is orally administered and has d...

Abstract 1857 This study is registered with ClinicalTrials.gov, number NCT00590187. Background: Sapacitabine is an orally administered nucleoside analogue with a unique ability to cause irreparable single-strand DNA breaks and induce G2 cell cycle arrest. We are conducting a multi-center, randomized phase 2 study to evaluate 3 dose regimens of this drug in older patients with MDS refractory to hypomethylating agents. The primary endpoint is 1-year survival. Secondary endpoints include the rate of CR, CRp, PR, CRi or hematological improvement (HI) and their corresponding durations. The study uses a selection design to identify a dose regimen which produces a better 1-year survival rate in the event that all three dose regimens are active. The planned sample size consists of 60 patients, 20 patients in each arm. Methods: Eligible patients must be ≥60 years with intermediate-2 or higher risk MDS previously treated with hypomethylating agents, ECOG 0–2, and adequate renal and hepatic functions. Patients were randomized 1:1:1 to receive sapacitabine every 3 –4 weeks at 200 mg b.i.d. × 7 days (Arm A), 300 mg b.i.d. × 7 days (Arm B), or 400 mg b.i.d. × 3 days per week × 2 weeks (Arm C). The number of cycles is not limited. Results: As of July 2010, 61 patients were treated with mean follow-up of 230 days. Median age was 73 years and 77% of patients were 70 or older. Baseline bone marrow contained < 5% blasts in 10 patients (16%), 5–10% blasts in 20 patients (33%), 11–20% blasts in 26 patients (43%) and 21–30% blasts in 5 patients (8%). The median number of cycles was 2 and 34% of patients received ≥ 4 cycles. To date, 14 patients have responded (2 CR and 12 major HIs) with response rates of: 24% (Arm A), 35% (Arm B) and 10% (Arm C). The two CRs occurred on Arm A. Median time to response is 2–3 cycles (range 1 to 6 cycles). Four deaths occurred within 30 days of randomization (7%), one of which was considered to be possibly related to sapacitabine. Common adverse events (all grades, regardless of causality) included fatigue, nausea, diarrhea, constipation, abdominal pain, anorexia, peripheral edema, dyspnea, alopecia, pneumonia, arthralgia, febrile neutropenia, anemia, neutropenia and thrombocytopenia, most of which were mild to moderate in intensity. Conclusions: Sapacitabine appears to be safe across all 3 dose regimens with the highest overall response rates observed on the 7-day dose regimens. Results for the primary endpoint of 1-year survival will be presented at the meeting. Disclosures: Wetzler: Cyclacel: Research Funding. Claxton:Cyclacel: Research Funding. Foran:Cyclacel: Research Funding. Goldberg:Cyclacel: Research Funding; Cyclacel: Research Funding. Chiao:Cyclacel: Employment, Equity Ownership. Kantarjian:Cyclacel: Research Funding.

Abstract 1061 Poster Board I-83 Introduction: Sapacitabine is a novel nucleoside analogue with a unique ability to cause irreparable single-strand DNA breaks and induce G2 cell cycle arrest. It is orally administered and has demonstrated promising anti-leukemic activity against relapsed or refractory AML and MDS in a phase 1 trial. We are conducting a multi-center, open-label, randomized phase 2 study to evaluate 3 dose regimens of this drug in elderly AML. The primary objective is to evaluate 1-year survival rate. The study uses a selection design to identify a dose regimen which produces a better 1-year survival rate in the event that all three dose regimens are active. The planned sample size consists of 60 patients or 20 patients in each arm. The study also uses a Bayesian continuous monitoring rule to stop accrual in one or more arms of the study in the event that a dose regimen does not have a sufficient number of responses. Patients and Methods: Eligible patients must be ≥70 years with AML previously untreated or in first relapse, ECOG 0-2, creatinine ≤ 1.5 x ULN, total bilirubin or direct bilirubin ≤ 1.5 x ULN and ALT ≤ 2.5 x ULN or ≤ 5 x ULN if the liver is involved by leukemic blasts. Patients were randomized 1:1:1 to receive one of the 3 dose regimens: 200 mg b.i.d. x 7 days every 3-4 weeks (Arm A), 300 mg b.i.d. x 7 days every 3-4 weeks (Arm B), or 400 mg b.i.d. x 3 days per week x 2 weeks every 3-4 weeks (Arm C). There is no limit on the maximum number of cycles. The primary efficacy endpoint is 1-year survival. Secondary efficacy endpoints include the rate of CR, CRp, PR, CRi or hematological improvement (HI) and their corresponding response durations. Results: Between December 2007 and October 2008, 60 elderly patients with AML were enrolled and treated. Median age was 77 and 35% of patients were 80 years or older. Fifty-one patients had previously untreated AML and 9 patients had AML in 1st relapse. The majority of the patients (87%) had intermediate/unfavorable risk karyotypes and 45% of AML were preceded by an antecedent hematological disease (AHD). As of August 2009, 9 patients are still on study. The median number of cycles was 3 and 18 patients (30%) received ≥ 6 cycles. Four patients (7%) discontinued treatment for unacceptable toxicity. The overall response rate is 45% on Arm A (10% CR, 35% PR/major HI), 25% on Arm B (10% CR/CRp, 15% PR/major HI), 35% on Arm C (25% CR, 10% major HI). Median time to response is 3 cycles (range 1-9). Eight deaths of all causes occurred within 30 days of randomization and one death was considered to be possibly related to sapacitabine. According to interim safety data, common adverse events (all grades, regardless of causality) included fatigue, nausea, diarrhea, anemia, febrile neutropenia, thrombocytopenia and peripheral edema, most of which were mild to moderate in intensity. Conclusion: Sapacitabine is safe and active across all 3 dose regiments with the highest CR rate observed on the 3-day dose regimen (Arm C). Mature 1-year survival data will be presented at the meeting. Disclosures: Kantarjian: Cyclacel, Inc.: Research Funding. Garcia-Manero:Cyclacel, Inc.: Research Funding. Chiao:Cyclacel, Inc.: Employment, Equity Ownership.

Background: Sapacitabine, a 2′-deoxycytidine nucleoside analogue with unique ability to cause irreparable single-strand DNA breaks and as a result induce G2 cell cycle arrest, is undergoing clinical evaluation for the treatment of cancer. The recommended Phase II dose (RD) in patients with advanced solid tumors was 75 mg twice daily (b.i.d.) x 7 days orally every 21 days. The major DLT was myelosuppression. Here, we present the initial results of a Phase I study of sapacitabine in patients with advanced leukemias or MDS. The primary objective was to define the MTDs of two dosing schedules, b.i.d. x 7 days orally every 21 days or b.i.d. x 3 days per week for 2 weeks every 21 days. The secondary objectives were to characterize the PK/PD effects of sapacitabine and its major metabolite CNDAC. Methods: Eligible patients had relapsed/refractory leukemias or MDS, or untreated disease if not willing to proceed with conventional systemic chemotherapy, adequate organ functions and performance status of 0–2. At least 3 patients were enrolled at each dose level. The MTD was the highest dose level at which ≤2/6 patients experienced a DLT during the first treatment cycle. Results: Forty-seven patients received sapacitabine, including 35 treated with the 7-day schedule and 12 treated with the 3-day per week schedule. Median age was 65 (range: 36 – 91). The majority of patients had AML (n=36) or MDS (n=4). Median number of prior chemotherapies was 2 (range: 0 – 6). Cytogenetic abnormalities were present in 27; 30 had relapsed disease or were refractory to cytarabine or high-dose cytarabine regimens. MTD was reached at 375 mg b.i.d. on the 7-day schedule, and 475 mg b.i.d. on the 3-day per week x 2 schedule. DLTs consist of abdominal pain/small bowel obstruction (n=1), neutropenic colitis (n=2) and diarrhea (n=3). One patient died from complications of neutropenic colitis. Common non-hematologic adverse events (all grades, regardless of causality) included fatigue, nausea, vomiting, diarrhea, anorexia, cough, dyspnea, and abdominal pain, most of which were mild to moderate in intensity. PK and PD data are being analyzed. To date, 11 patients of 42 evaluable (9 AML, 2 MDS) had a reduction in bone marrow blast counts to ≤ 5% including 2 CRs, 2CRs with incomplete recovery of platelets, 1 CR of extramedullary disease, and 1 PR of extramedullary disease. 5/11 had relapse-resistance disease on prior cytarabine. Conclusion: The MTD of sapacitabine is 375 mg b.i.d. by the 7-day schedule and 475 mg b.i.d. by the 3-day per week schedule. The predominant DLT is gastrointestinal toxicity. Sapacitabine is well tolerated and has promising antileukemic activity in patients with relapsed or refractory AML and MDS.

7063 Background: Sapacitabine, a 2′-deoxycytidine nucleoside analogue with unique ability to induce G2 cell cycle arrest and cause irreparable single-strand DNA breaks, is undergoing clinical evaluation for the treatment of cancer. The recommended Phase II dose (RD) in patients with advanced solid tumors was 75 mg b.i.d.×7 days orally every 21 days. The major DLT was myelosuppression. Here, we present the initial results of a Phase I study of sapacitabine in patients with advanced leukemias or MDS. The primary objective was to define the MTD of the above dosing schedule and the secondary objectives were to characterize the PK/PD effects of sapacitabine and its major metabolite CNDAC. Methods: Eligible patients had relapsed/refractory leukemias or MDS, or untreated disease if not willing to proceed with conventional systemic chemotherapy, adequate organ functions and performance status of 0–2. At least 3 patients were enrolled at each dose level. The MTD was the highest dose level at which =2/6 patients experienced a DLT during the first treatment cycle. Results: Twenty- nine patients received sapacitabine. Median age was 64 (range: 36 - 91). The majority of patients had AML (n=24) or MDS (n=4). Median number of prior chemotherapies was 2 (range: 0 - 6). MTD was reached at the dose level of 375 mg b.i.d. with 2/7 patients experienced the DLT of small bowel obstruction (n=1) or neutropenic colitis (n=1). One patient died from complications of neutropenic colitis. Common non-hematologic adverse events (all grades, regardless of causality) included nausea, vomiting, diarrhea, anorexia, alopecia, and fatigue, most of which were mild to moderate in intensity. PK and PD data are being analyzed. To date, 7 patients (5 AML, 2 MDS) had a reduction in bone marrow blast counts to = 5% including 1 CR in refractory AML with incomplete platelet recovery and 1 CR in relapsed MDS. In addition, 2 AML patients with relapsed leukemia cutis had a significant reduction in leukemia infiltrates in skin. Conclusion: The RD of sapacitabine for the b.i.d.×7 days every 21 days schedule is 325 mg b.i.d. The DLT is gastrointestinal toxicity. Sapacitabine is well tolerated and has promising antileukemic activity in patients with relapsed or refractory AML and MDS. No significant financial relationships to disclose.

There is no standard of care for older patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive therapy, and prognosis with currently recommended low-intensity therapies (decitabine, azacitidine, and low-dose cytarabine [LDAC]) remains poor. One promising strategy is to combine low-intensity treatments with novel agents. Gemtuzumab ozogamicin, tipifarnib, and barasertib have been investigated in phase 2/3 or 3 trials combined with LDAC, and phase 3 trials are currently investigating sapacitabine plus decitabine, and volasertib plus LDAC in AML. This review discusses current treatment recommendations and the development of combination therapies for older patients unfit for intensive therapy.