Webster, Jonathan

Abstract Background: Relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) remain challenging to treat, particularly in older patients and those with a T-cell phenotype. Venetoclax (VEN), a selective BCL-2 inhibitor, has shown preclinical synergy with vincristine (VCR) in multiple preclinical ALL models. Following the previously reported establishment of the recommended Phase II dose (RP2D), we now report the results of the Phase II (Ph2) portion of EA9152 (VEN 600 mg daily with weekly L-VCR 2.25 mg/m² IV or VCR 1.5 mg/m2 IV capped at 2 mg), evaluating efficacy and safety in this high-risk population. Methods: This open-label, multicenter Phase II study enrolled adults (≥18 years) with R/R B- or T-cell ALL or LL. The phase II portion of this trial was a single-arm, open-label study evaluating the combination of VEN (600 mg po D1–28) with either L-VCR (2.25 mg/m² IV weekly x4) or vincristine sulfate (VCR) (1.4 mg/m² IV weekly x4). Following the market withdrawal of L-VCR in the United States in April 2022, no new patients were initiated on this formulation and patients already receiving L-VCR were transitioned to VCR at the start of their next treatment cycle or sooner if necessitated by drug availability. Prior VCR but not VEN exposure was permitted in Ph2. The primary endpoint was achievement of a complete response or complete response with incomplete count recovery CR + CRi rate by end of cycle 3. Secondary endpoints included measurable residual disease (MRD) response, progression free survival (PFS), overall survival (OS), and safety. The association of phenotype with response and time-to-event were evaluated using Fisher's exact test and the Cox proportional hazards model, respectively. Results: Twenty-one eligible patients were treated (B-cell ALL/LL: n=12; T-cell ALL/LL: n=9). The trial was terminated early after 22/56 patients were accrued on account of withdrawal of sponsor support. Median age was 50 years and 76.2% were male. Performance status was 0–1 in 85.7%. All patients had received prior chemotherapy; 47.6% had undergone prior transplant. Median number of treatment cycles was 1 (2 for B-cell, 1 for T-cell). By end of cycle 3, no patients in the B-cell cohort (0/12; 90% CI, 0.00–0.22) achieved CR or CRi, 8 had stable disease (SD). In the T-cell cohort, 1 of 9 patients (11.1%; 90% CI, 0.01–0.43) achieved CR, 1 achieved PR and 1 had SD. There was no statistically significant difference in CR + CRi rate between phenotypes (p=0.43). None of the patients achieved an MRD-negative CR/CRi by flow cytometry or molecular methods. At the time of this analysis, 16 of 21 patients had died. Median overall survival (OS) was 4.3 months (95% CI, 1.5–22.0) for B-cell and 10.2 months (95% CI, 2.0–16.4) for T-cell patients (HR 1.32, p=0.60). Median PFS was 2.9 months (95% CI, 1.7–3.7) for B-cell and 1.2 months (95% CI, 0.7–4.6) for T-cell cohorts (HR 2.18, p=0.18). Grade 3–5 treatment-related adverse events occurred in most patients. One T-cell patient experienced grade 5 respiratory failure. Among 16 patients enrolled under the revised protocol using VCR, only 1 experienced grade 3 peripheral motor neuropathy, and no peripheral sensory neuropathy was reported (combined AE rate 0.06; 90% CI, 0.00–0.26). Tumor lysis syndrome was not observed in this cohort. Conclusions: The combination of VEN at the established RP2D and L-VCR/VCR was feasible and had an acceptable safety profile in heavily pretreated patients with R/R ALL/LL. However, response rates, including CR/CRi and MRD negativity, were limited, particularly in the B-cell cohort. Median OS and PFS remain poor in both subtypes, highlighting the need for improved strategies in this high-risk population. Venetoclax, in combination with other chemotherapy regimens, has shown encouraging response rates warranting continued exploration of its benefit in ALL.

Abstract DAC combinations serve as frontline therapies for AML. DAC forms DNA-DNMT1 crosslinks and activates the ATR-CHK1-WEE1 DDR. Combinations of DNA-protein crosslinking agents with ATR, CHK1, or WEE1 inhibitors (i) have shown efficacy in solid tumors. This study evaluates the cytotoxic synergy of DAC plus ATRi, CHK1i, or WEE1i in AML. Public datasets were queried for mRNA expression and dependency. Commercial cell lines (U937, KG1a, Molm13, MV-4-11) were genomically validated. Molm13 TP53-/- clones were generated via CRISPR. Cells were cultured in complete RPMI. To treat, cells were cultured for 48 h in RPMI with drugs or diluent (0.2% v/v DMSO). Protein expression was evaluated by Western blotting (WB). Apoptosis was assayed by flow cytometry with annexin V or propidium iodide. Primary AML samples were obtained at study centers after informed consent. Isolated mononuclear cells (Ficoll) were used in colony forming unit (CFU) assays with DMSO or drug for 12-16 days. Synergy was determined by median-effect (CalcuSyn) where a combination index <1 is synergistic and >1 antagonistic. DNMT1 expression (TCGA) was highest in AML vs all other tumor types (p<0.001). In CRISPR screens (DepMap), AML cell lines were increasingly dependent on DNMT1, ATR, CHK1, and WEE1 (ANOVA p<0.001). WB of AML cell lines treated with DAC (25 - 200 nM) for 24 h showed phosphorylations of H2AX and CHK1 S296/S345 that were most pronounced in TP53MT lines. In apoptosis assays, ATRi, CHK1i, and WEE1i were synergistic with clinical concentrations of DAC (Table 1). In isogenic Molm13 lines, TP53 loss conferred DAC resistance that was overcome with combination treatment. Selective CHK1i were generally more synergistic than CHK1/2i, consistent with a CHK1 DDR. CFU assays of primary AML samples also showed synergy between DAC and ATRi, CHK1i, and especially WEE1i. Table 1. Synergy between decitabine and replication checkpoint inhibitors in preclinical models of AML. Cell line data are derived from subdiploid apoptosis assays. U937 data were replicated using annexin V. Prexasertib showed no activity in KG1a cells (suggesting drug efflux) requiring the use of the alternate CHK1 inhibitor, rabusertib. Abbreviations: ATR, ataxia telangiectasia and Rad3 related; CHK1/2, checkpoint kinase 1 and/or 2; CI, combination index; Conc, concentration; DNMT1, DNA methylatransferase 1; IQR, interquartile range; MT, mutated; ND, not determined; SD, standard deviation; WT, wild type. Drug Target Conc. (nM) Molm13 (TP53WT) Molm13 (TP53-/-) U937 (TP53G187fs*/-) KG1a (TP53V225fs*/-) Primary AML (TP53WT orTP53MT) Units Decitabine DNMT1 6.25 – 200 25 ± 11 350 ± 260 310 ± 180 6.1 ± 1.6 ND EC50, nM (mean, SD) Ceralasertib ATR 250 – 500 0.93 (0.66 – 1.24) 0.90 (0.84 – 0.96) 0.15 (0.08 – 0.21) 0.74 (0.63 – 1.02) 0.66 (0.43 – 2.43) CI with decitabine (median, IQR) Camonsertib ATR 10 – 100 0.27 (0.19 – 0.59) 0.24 (0.22 – 0.34) 0.34 (0.21 – 0.39) ND ND Prexasertib CHK1/2 1.0 – 6.0 0.89 (0.82 – 1.06) 0.78 (0.68 – 0.90) 0.95 (0.93 – 1.08) ND 0.88 (0.29 – 1.28) MK-8776 CHK1 250 – 1, 000 0.57 (0.48 – 0.80) 0.76 (0.73 – 1.19) 0.89 (0.57 – 1.39) ND ND Rabusertib CHK1 600 – 1, 000 ND ND ND 0.51 (0.48 – 0.56) ND Adavosertib WEE1 100 – 400 0.70 (0.63 – 1.11) 0.99 (0.78 – 1.14) 0.67 (0.60 – 0.74) 0.67 (0.37 – 0.93) 0.65 (0.43 – 0.88) DAC synergizes with ATRi, CHK1i, and WEE1i in AML. Future work will test these combinations in vivo and incorporate BH3 mimetics. Citation Format: Clifford M. Csizmar, Antoine N. Saliba, Olivia K. Rossman, Kevin L. Peterson, X. Wei Meng, B. Douglas Smith, Gabriel Ghiaur, Jonathan A. Webster, Mrinal M. Patnaik, Aref Al-Kali, Scott H. Kaufmann. Decitabine (DAC) induces a DNA damage response (DDR) and synergizes with replication checkpoint inhibitors in acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1170.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

AbstractIntroductionRelapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B‐ and T‐ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L‐VCR and VEN for patients with r/r B‐or T‐cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644).MethodsIn a 3+3 dose escalation design, r/r ALL subjects were given single‐agent VEN doses reaching 400, 600, or 800 mg for the three respective dose levels. Weekly L‐VCR at 2.25 mg/m2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination.ResultsAmong the 18 patients in phase I, grade ≥ 3 treatment‐related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose‐limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600 mg). Twenty‐two percent of evaluable patients (N = 4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD).ConclusionThe combination of VEN and L‐VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L‐VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate.

AbstractBackgroundDespite recent approval of several new agents, relapsed acute lymphoblastic leukemia (ALL) remains challenging to treat. Sapanisertib (MLN0128/TAK‐228) is an oral TORC1/2 inhibitor that exhibited preclinical activity against ALL.MethodsWe conducted a single‐arm multi‐center Phase II study of sapanisertib monotherapy (3 mg orally daily of the milled formulation for 21 days every 28 days) in patients with ALL through the Experimental Therapeutics Clinical Trials Network (NCI‐9775).ResultsSixteen patients, 15 of whom were previously treated (median 3 prior lines of therapy), were enrolled. Major grade 3–4 non‐hematologic toxicities included mucositis (3 patients) and hyperglycemia (2 patients) as well as hepatic failure, seizures, confusion, pneumonitis, and anorexia (1 patient each). Grade >2 hematological toxicity included leukopenia (3), lymphopenia (2), thrombocytopenia, and neutropenia (1). The best response was stable disease in 2 patients (12.5%), while only 3 patients (19%) were able to proceed to Cycle 2. Pharmacokinetic analysis demonstrated drug exposures similar to those observed in solid tumor patients. Immunoblotting in serially collected samples indicated limited impact of treatment on phosphorylation of mTOR pathway substrates such as 4EBP1, S6, and AKT.ConclusionIn summary, single‐agent sapanisertib had a good safety profile but limited target inhibition or efficacy in ALL as a single agent. This trial was registered at ClinicalTrials.gov as NCT02484430.

Abstract Background: Relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remain a therapeutic challenge, especially in elderly patients(pts) or those with T-cell immunophenotype. Inhibition of apoptosis is an increasingly recognized mechanism for resistance to conventional chemotherapy. Recently, the oral bcl-2 inhibitor venetoclax (VEN) has shown remarkable activity in a variety of hematologic malignancies. Preclinical data in both B- and T-ALL suggests synergy of VEN with vincristine(VCR). Liposomal VCR (L-VCR) is FDA approved for relapsed ALL having progressed following 2 or more antileukemia therapies. We designed a phase I/II trial (EA9152) of the combination of L-VCR and VEN for pts with r/r B-or T-cell ALL or LL. Here, we report for the first time the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644). Methods: This open-label phase I/II study enrolled pts age>=18 with ALL or LL who were R/R to multiagent chemotherapy. Subjects could have received prior VCR or VEN . In a standard 3 + 3 dose escalation design, subjects were given a two week lead-in phase of single agent VEN in the following schedule: dose level 1 - 20, 50, 100, 200 mg on days 1, 2, 3, 4 and 400 mg on days 5 ‒ 42; dose level 2 - 50, 100, 200, 400 mg on days 1, 2, 3, 4 and 600 mg on days 5 ‒ 42; and dose level 3 ‒ 100, 200, 400, 600 mg on days 1, 2, 3, 4 and 800 mg on days 5 ‒ 42. Weekly L-VCR 2.25mg/m 2 IV was started on D15 of cycle 1, and starting day 1 for subsequent cycles (cycle 2+ = 28 days). For cycle 2 and beyond, VEN 400mg, 600mg, or 800mg based on dose level was given starting on day 1 of the cycle. Primary objective of the phase I portion was to determine the maximum tolerated dose (MTD) of VEN in combination with L-VCR. Secondary objectives included determining preliminary response rates. Results: EA9152 was activated on April 26, 2018 and the phase I portion closed to accrual on March 2, 2021. Among the 18 pts in dose escalation (Table 1), the median age was 42 years (22-77). The majority of pts were male (56%), white (80%), and with a performance status (PS) of 1 (78%). Among 13 pts with disease diagnosis reported, 9 had ALL and 4 had LL. Seventeen of 18 (94%) reported previous chemotherapy, two of which had previous stem cell transplant. Median treatment cycles received is 1 (range 1-11). One patient, having received 11 cycles, remains on study at the time of data analysis. Grade >=3 treatment-related adverse events were reported in 89% of treated pts, with neutrophil count decreased (67%), white blood cell decreased (56%), and anemia (50%) as the most common. One pt experienced grade 3 tumor lysis syndrome. Twelve pts were considered evaluable for MTD determination. Six pts were considered not evaluable for toxicity analysis on account of withdraw of consent for treatment (n=4) or rapid disease progression (n=2). Two pts (2 of 3) at dose level 3 experienced DLTs, one each of hypokalemia and heart failure. Therefore, the MTD of the combination was determined to be dose level 2 - VEN 50, 100, 200, 400 mg on days 1, 2, 3, 4 and 600 mg on days 5 ‒ 42 and for subsequent cycles, with L-VCR 2.25mg/m2 IV weekly. In regards to best overall responses observed (Table 2) 4 of 18 pts (22%) achieved complete response (CR), 4 patients (22%) had stable disease, and 7 (39%) had progressive disease. Two patients in CR were found to be measurable residual disease (MRD) negative as well. Conclusions: In the phase 1 portion of this study, the combination of VEN and L-VCR was found to be safe for patients with ALL and LL. The MTD of the combination was found to be VEN 600mg daily with encouraging preliminary efficacy seen including MRD negative responses. The phase 2 portion of this trial is actively enrolling with VEN 600mg daily starting C1D1. Figure 1 Figure 1. Disclosures Palmisiano: Takeda: Consultancy; Genentech: Research Funding; Foundation One: Consultancy; AbbVie: Consultancy, Research Funding. Claxton: Astellas: Other: Clinical Trial; Novartis: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Incyte: Research Funding. Park: BMS: Consultancy; Amgen: Consultancy; Autolus: Consultancy; Novartis: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Kite Pharma: Consultancy; Kura Oncology: Consultancy; Affyimmune: Consultancy; Servier: Consultancy; Innate Pharma: Consultancy; Intellia: Consultancy. Podoltsev: Novartis: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Blueprint Medicines: Honoraria; Bristol-Myers Squib: Honoraria; PharmaEssentia: Honoraria; CTI BioPharma: Honoraria. Atallah: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy. Dinner: Kite/Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Webster: AmGen: Consultancy; Pfizer: Consultancy. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Litzow: AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. OffLabel Disclosure: Venetoclax, a BCL-2 inihibitor, is not FDA-approved for use in ALL.

Abstract Although inhibitors of the kinases CHK1, ATR, and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines in vitro, including TP53-null acute myeloid leukemia (AML) and BCR/ABL–positive acute lymphoid leukemia (ALL), and inhibits leukemic colony formation in clinical AML samples ex vivo. In further studies, downregulation or inhibition of CHK1 triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNFα production, and engagement of a TNFR1- and BID-dependent apoptotic pathway. AML lines that were intrinsically resistant to CHK1 inhibition exhibited high CHK1 expression and were sensitized by CHK1 downregulation. Signaling through this same CDK2–AP1–TNF cytotoxic pathway was also initiated by ATR or WEE1 inhibitors in vitro and during CHK1 inhibitor treatment of AML xenografts in vivo. Collectively, these observations not only identify new contributors to the antileukemic cell action of CHK1, ATR, and WEE1 inhibitors, but also delineate a previously undescribed pathway leading from aberrant CDK2 activation to death ligand–induced killing that can potentially be exploited for acute leukemia treatment. Significance: This study demonstrates that replication checkpoint inhibitors can kill AML cells through a pathway involving AP1-mediated TNF gene activation and subsequent TP53-independent, TNFα-induced apoptosis, which can potentially be exploited clinically.

e18506 Background: Sapanisertib (SAP) is an oral small molecule dual mTOR complex 1 and 2 (TORC1/2) inhibitor that showed activity in lymphoid neoplasms. It blocks a feedback loop involving mTORC2 activation when TORC1 is selectively inhibited (Yun S et al, Blood 2016). SAP induces apoptosis of malignant lymphoid cells in vitro and in xenografts, with greatest effects in ALL cell lines. We aim to assess potential efficacy of SAP when used as a single agent in relapsed/refractory ALL. Methods: Adults (age ≥18) with ECOG performance status 0-2 and normal organ function (creatinine/total bilirubin <1.5 upper limit of normal) with relapsed and/or refractory ALL (B- or T-cell) were enrolled. Newly diagnosed patients (pts) unfit for aggressive treatments and BCR-ABL+ ALL were allowed if there was no suitable standard treatment. SAP was given at 3 mg orally daily for 21 days every 28 days. Dose escalation was allowed after 2 cycles. Hydroxyurea and corticosteroids were not allowed after starting SAP. The primary end point was complete remission (CR) or CR with incomplete count recovery (CRi). This is a one stage Simon design study with interim analysis after 11 pts completed treatment. Enrollment was continued until interim analysis was done. Results: A total of 16 pts were enrolled on the study with a median age of 46 years old, 56% being males. 1/16 (6%) was treatment naïve. Median number of prior therapies is 3 (range, 1-9). The mean duration on SAP was 14.7 days (range 1-22). Three pts were able to start cycle 2. Safety was evaluable in 14 pts. All 14 pts had at least one G3 AE, while 10 pts had at least one G4 AE. G3/4 related non-hematological adverse events (AE) included 3 mucositis, 1 hepatic failure, 1 sepsis, 3 hyperglycemia, 1 anorexia, 1 seizure, 1 confusion, and 1 pneumonitis. One pt had G5 AE with malignancy. G3/4 hematological AEs included 2 with lymphopenia, 1 thrombocytopenia, 3 with leukopenia, and 1 with neutropenia. No pt achieved a CR/CRi. Best response was stable disease in 2 (12.5%) pts. Five pts had progressive disease while 9 were not evaluable because of early removal. Conclusions: SAP exhibited the expected safety profile. Although several pts developed cytopenias on drug, there was no evidence of clinically meaningful single-agent activity against ALL. Analysis of paired bone marrow aspirates from this trial is being performed to assess whether mTOR was substantially inhibited at therapeutically achievable drug concentrations. Clinical trial information: NCT02484430.

Abstract Background: Cytosine arabinoside (ara-C) remains the backbone of most regimens for the treatment of AML. The incorporation of ara-C into DNA activates checkpoint kinase 1 (Chk1) causing replication fork slowing, the accumulation of cells in S phase, and diminished ara-C cytotoxicity. The selective Chk1 inhibitor MK-8776 abrogates ara-C-induced S-phase arrest, thereby enhancing ara-C-induced apoptosis in vitro.1 A phase I trial demonstrated the safety of MK-8876 in combination with infusional ara-C and correlative studies demonstrated increased ara-C-induced H2Ax phosphorylation in AML cells, consistent with unrepaired DNA damage.2 Herein, we report data from a phase II trial comparing ara-C plus MK8876 with ara-C alone. Methods: Patients with relapsed or refractory AML were randomized to receive either ara-C 2 gm/m2 via continuous infusion (CIV) over 72 hours on days 1 and 10 with MK-8776 100 mg flat dose infused over 30 minutes on days 2, 3, 11, and 12 (combo); or ara-C alone on the same schedule (control). The primary end point was response rate (CR+CRi). Adverse events (AEs) for all patients were reported according to the NCI-CTCAE version 4.0. Correlative studies were performed on blood and marrow samples collected prior to treatment on days 1, 2 and 3 and at one hour after MK-8776 infusion (PB only). Marrow and circulating blasts were analyzed using semi-quantitative flow cytometric determinations of blast cell gH2AX expression, a marker of DNA damage. Results: Thirty-two patients were treated at 4 sites with 14 assigned to the combo arm and 18 to the control arm. The study was stopped early due to lack of drug availability. The median age was 60 (range 29-72) and 17 (53%) were male. Nine (28%) had refractory AML, 16 (50%) were in first relapse, and 7 (22%) were in second relapse. Eleven (34%) had undergone a prior bone marrow transplant (BMT). Risk stratification classified 1 (3%) patient as favorable risk disease, 11 (34%) as intermediate-1, 8 (25%) as intermediate-2, and 11 (34%) as adverse risk. There were 5 (36%) responses (CR/CRi) and 1 (7%) partial response (PR) in the combo arm, and 8 (44%) responses and 1 (6%) PR in the control arm. Median survival did not differ significantly between the two groups (5.9 months in the combo arm vs. 4.2 months in the control arm). Sub-group analysis showed increased responses in the combo arm for the patients in first relapse (50% vs. 40%) and those with a prior BMT (50% vs. 29%). Most non-hematologic grade 3/4 treatment-related AEs were similar in the two groups including febrile neutropenia (64% vs. 61%), infectious complications (50% vs. 50%), and sepsis (21% vs. 17%). Patients in the combo arm experienced more QT prolongation (21% vs. 0%), hypertension (21% vs. 0%), and GI toxicities (21% vs. 0%); while those in the control arm had increased renal (0% vs. 11%) and liver toxicity (7% vs. 17%). Two deaths were attributed to treatment, and both were in the control arm. Eight combo patients had serial PB samples and 2 had serial marrow samples studied by flow cytometry. There was an increase in the percentage of gH2AX+ CD34+ cells on Day 2 directly after MK-8876 infusion (16.9% prior and 36.4% at one hour), which occurred to a lesser extent on Day 3 after MK-8876 infusion (12.7% prior and 15.6% at one hour). Three of eight patients demonstrated a sustained increase in gH2AX+ CD34+ from Day 2 to Day 3, and all three achieved either a PR or CR. Conclusion: This is the first phase II study building on prior work suggesting that inhibition of Chk1 would increase response to ara-C in patients with relapsed or refractory AML. The study confirmed that treatment with the combination is feasible with similar toxicities between the treatment and control groups. The response rates were similar between the two groups with improved responses in patients receiving the combo in first relapse and following BMT. Correlative studies support the finding that responding patients show a sustained increase in DNA damage and this may serve as a biomarker in future studies. Chk1 remains a potential target to improve treatment outcomes with ara-C. References: 1. Schenk EL et al. Clin Cancer Res. 2012 Oct 1; 18(19):5364-73. 2. Karp JE et al. Clin Cancer Res. 2012 Dec 15; 18(24):6723-31. Disclosures No relevant conflicts of interest to declare.