Feldman, Eric J.

Background: Recent advancements in multiple myeloma (MM) diagnosis and treatment significantly improved patients' survival and quality of life. Severe Renal Impairment (RI) remains a significant challenge in newly diagnosed MM (NDMM), complicating treatment and affecting outcomes. Prior studies reported improved overall renal recovery in the era of novel therapies. However, there is a lack of evidence documenting the outcomes of patients presenting with severe RI. We present an updated analysis of the characteristics and outcomes of patients with NDMM presenting with severe RI in an ethnically diverse, low socio-economic population. Methods: A single-center retrospective review of patients with NDMM presenting to Montefiore Medical Center (Bronx, New York) was conducted from 2011-2023. Severe RI was defined as an estimated glomerular filtration rate (eGFR) of less than 30 mL/min/1.73 m². MM risk was assessed using the mSMART 3.0 tool. Results: Out of 284 patients with NDMM, 58 (20%) patients presented with severe RI. Black patients (p = 0.018) and older adults (64 years vs 60 years, p value 0.032) were more likely to present with severe RI. Severe RI at diagnosis correlated with high-risk myeloma (p = 0.002), high R-ISS stage (p < 0.001), and a lower likelihood of receiving stem cell transplants (p < 0.001). Among those with severe RI, 23/58 required dialysis of which 6/23 were taken off dialysis at last follow-up after renal recovery. Median eGFR at diagnosis, 6 months and 1 year after diagnosis was 11, 23 and 23.5 ml/min/1.73 m2, respectively. 14 out of 58 patients (39%) achieved renal recovery to eGFR > 30 one year post-diagnosis, with no significant difference in race, sex, or ethnicity. The most common first-line treatment for patients with severe RI was CyBorD (62%). The median time from diagnosis to first treatment (including plasma exchange) was 10 days. By the last follow-up, 35/58 patients (60%) had a stem cell transplant, with a median time from diagnosis to transplant of 275 days. The median overall survival (OS) for patients with severe RI at diagnosis was 49 months, while it was not reached for those without severe RI (p < 0.001). Early death (≤ 2 months after diagnosis) occurred in 2 patients, both with severe RI. Among patients with severe RI, multivariate Cox regression survival analysis showed that achieving free light chain (FLC) below 500 mg/L (HR 0.212, p < 0.001) and receiving a stem cell transplant (HR 0.209, p 0.002) improved outcome. Conclusions: Despite improvements in the life expectancy of patients with MM, severe renal failure remains a challenge, particularly among minorities. Socioeconomic factors need to be explored as a contributor to outcomes in patients with severe RI. Achieving FLC clearance and undergoing stem cell transplant may play a role in survival in patients with NDMM and severe RI.

Abstract T is a Farnesyltransferase inhibitor with clinical activity in elderly adults with newly diagnosed AML who are not candidates for TCC. For adults ≥ age 65 with poor-risk AML, T 600 mg BID for 21 out of every 28–63 days induces complete remissions (CR) in 15%, median duration 7.3 mos, median survival 18 mos. In vitro, T+E exhibits synergistic anti-AML effects. In an attempt to increase CR rates in elderly AML pts, we are conducting a Phase I trial of oral T+E, with escalating doses of both drugs and 14 vs. 21 days of T every 28–63 days (median time to beginning cycle 2 is Day 31, range 29–43). To date, 60 adults ≥ age 70 (median 77, range 71–91) have been treated at 10 dose levels of T (300, 400 or 600 mg BID, 14 or 21 days) + E (100, 150 or 200 mg daily days 1–3 and 8–10) and have received 145 cycles (median 3, range 1–7). A total of 35 (58%) have had secondary AML and 31 (52%) have had adverse cytogenetics. Marrow blast percent was median 55% (range 20–96%), with 75% >30,000 blasts. Nonhematologic toxicities include oropharyngeal mucositis (15% ≥ grade 2), CNS (overall 30%, with 80% of those ≤ grade 2), renal (6%), hyperbilirubinemia (6%), rash (20%) and fatigue (20%). Toxicities occurred across all T+E dose levels tested to date. Documented infections occurred in 16 (27%) pts during cycle 1 and 22/145 (14%) cycles. Twenty six pts (43%) required hospitalization during cycle 1 for median 7 days (range 2–28). Overall hospitalization rate for all cycles was 28% (41/145). Ten pts (17%) died on study: 6 during cycle 1 (4 infection, 1 emphysema, 1 cerebrovascular) and 4 during cycles 2–4 (3 acute myocardial infarctions, 1 ventricular arrhythmia). For 56 evaluable pts, 12 (21%) have achieved CR and 11(20%) have achieved partial remission/hematologic improvement (PR/HI). All pts achieving CR have done so within 2 cycles (9/12 after cycle 1). Eight of 30 pts (27%) receiving T ≥ 400 mg BID have achieved CR. Median age of CR pts is 79 (range 71–86), 8 (67%) have secondary AML, and 5 (42%) have complex cytogenetics. CR durations to date range from 2+ to 13.5+ mos, with median 7+ months. Three of 12 have relapsed at 3, 10, and 11 mos, 2 have been retreated with T+E, and both have achieved 2nd CRs. In sum, the oral regimen of T+E is tolerable and feasible on an outpatient basis for elderly adults with newly diagnosed AML who are not candidates for TCC, with the suggestion of improvement of CR rates over T alone.

Abstract Background SGI-110 is second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine delivered as a small volume, pharmaceutically stable SQ injection allowing longer half-life and more extended decitabine exposure than DAC IV infusion. SGI-110 differentiated pharmacokinetic profile resulted in potent hypomethylation and clinical responses in previously treated MDS and AML patients in the phase 1 trial (Kantarjian et al. 2012). Methods In a randomized Phase 2 study, relapsed/refractory AML, or elderly treatment naïve AML patients who were not suitable for induction chemotherapy (poor major organ function; poor cytogenetics; or secondary AML) were randomized to one of two SQ doses – the biologically effective dose (BED) of 60 mg/m2 QDx5 or 90 mg/m2 QDx5. The primary endpoint of the phase 2 study is the overall remission rate (CR, CRi, and CRp) based on the International Working Group Criteria 2003. Safety findings based on adverse events (AEs) as graded by the CTCAE v4 criteria and pharmacodynamic data on Long Interspersed Nucleotide Element (LINE-1) DNA methylation (an index of global DNA methylation) activity were also assessed and reported. Results As of June 30, 2013, sixty-seven patients (50 relapsed/refractory AML, 17 treatment naïve elderly AML) were treated and had a minimum follow up of 3 months. Patients were randomized to either 60 mg/m2 dose (32 patients) or 90 mg/m2 dose (35 patients). The median age was 66 years (range, 22–84), 69% were male, and ECOG PS of 0/1/2 was reported in 11/47/9 patients respectively. Median number of prior regimens was 2 (range, 0–10). Patients’ characteristics were well balanced between the 2 dose groups. The primary endpoint of overall remissions (CR, CRp, or CRi) was observed in 17/67 patients (25% with 95% CI, 16–37%). There were 8 complete remissions (CR, CRp, or CRi) in 50 patients with relapsed/refractory AML (16% with 95% CI, 7-29%); and 9 complete remissions (CR, CRp, or CRi) in 17 treatment-naïve elderly AML patients (53% with 95% CI, 28-77%). Five patients (4 relapsed/refractory, and one treatment-naïve elderly AML) subsequently received a stem cell transplant. There was no difference in the complete remission rate between 60 and 90 mg/m2 doses (8 remissions in 32 patients at 60 mg/m2, and 9 remissions in 35 patients at 90 mg/m2). LINE-1 DNA methylation data before and after treatment was available in 50 (75%) patients enrolled. LINE-1 demethylation ≥ 10% post treatment was observed in 83% and 78% in the 60 mg/m2 and 90 mg/m2, respectively. The median maximum LINE-1 demethylation for responders is 25% as compared to 19% for non-responders. The most common adverse events (AEs) regardless of relationship to SGI-110 ≥ Grade 3 include febrile neutropenia, thrombocytopenia, anemia, leukopenia, neutropenia, and pneumonia. The 90 mg/m2 dose showed a greater frequency of Grade 3/4 related AEs ≥ 10% (anemia, febrile neutropenia, leukopenia, neutropenia, and thrombocytopenia) compared to the 60 mg/m2 dose. Conclusions SQ SGI-110 is a new HMA which is well tolerated and clinically active in the treatment of AML. Complete remissions and potent demethylation of ≥10% were equally observed at the 2 dose groups of 60 and 90 mg/m2. These data support further phase 3 investigation of this agent in the treatment of AML. Preliminary overall remission rate of 53% in treatment-naïve elderly AML seems to compare favorably with previous results reported for HMA treatment but this needs to be confirmed in a larger number of patients and randomized studies. Disclosures: Kantarjian: Astex Pharmaceuticals, Inc.: Research Funding. Jabbour:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Kropf:Astex Pharmaceuticals, Inc.: Research Funding. O'Connell:Astex Pharmaceuticals, Inc.: Research Funding. Stock:Astex Pharmaceuticals, Inc.: Research Funding. Tibes:Astex Pharmaceuticals, Inc.: Research Funding. Rizzieri:Astex Pharmaceuticals, Inc.: Research Funding. Walsh:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Roboz:Astex Pharmaceuticals, Inc.: Honoraria, Research Funding. Savona:Astex Pharmaceuticals, Inc.: Research Funding. Ervin:Astex Pharmaceuticals, Inc.: Research Funding. Podoltsev:Astex Pharmaceuticals, Inc.: Research Funding. Pemmaraju:Astex Pharmaceuticals, Inc.: Research Funding. Daver:Astex Pharmaceuticals, Inc.: Research Funding. Garcia-Manero:Astex Pharmaceuticals, Inc.: Research Funding. Borthakur:Astex Pharmaceuticals, Inc.: Research Funding. Wierda:Astex Pharmaceuticals, Inc.: Research Funding. Ravandi:Astex Pharmaceuticals, Inc.: Research Funding. Cortes:Astex Pharmaceuticals, Inc.: Research Funding. Brandwein:Astex Pharmaceuticals, Inc.: Research Funding. Odenike:Astex Pharmaceuticals, Inc.: Research Funding. Feldman:Astex Pharmaceuticals, Inc.: Research Funding. Chung:Astex Pharmaceuticals Inc.: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Choy:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Dimitrov:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Issa:Astex Pharmaceuticals, Inc.: Consultancy, Research Funding.

Abstract Background SGI-110 is a second generation HMA formulated as a dinucleotide of decitabine (DAC) and deoxyguanosine. The compound is delivered as a small volume, pharmaceutically stable subcutaneous (SQ) injection which allows longer half-life and more extended DAC exposure than DAC intravenous infusion. This pharmacokinetic profile offers the potential for improved biological and clinical activity and safety over currently available HMAs (Kantarjian et al. ASH, 2012). Methods A randomized Phase 1-2 first-in-human PK/PD-guided, dose-escalation study was conducted in patients with relapsed or refractory intermediate or high-risk MDS or AML. Patients were initially randomized to one of two SQ regimens - Dailyx5 or Weeklyx3, for 28-day courses. Subsequently, a Twice Weeklyx3 regimen (Monday, Thursday) was added for evaluation based on emerging LINE-1 demethylation data from the Weeklyx3 regimen. Results 93 patients (74 AML, 19 MDS) were treated in the dose escalation phase: 44, 34, and 15 patients were treated in the Dailyx5, Weeklyx3, and the Twice Weeklyx3 regimens, respectively. Across the three regimens, median age was 70 years (range, 29–86), 68% male, and 87% had ECOG PS of 0-1. The median number of prior regimens was 3 (range, 1–9) and 68% of patients had prior HMA treatment (59% AML, and 100% MDS). Of the 74 AML patients treated, 31 (42%) had secondary AML including antecedent MDS. Patients received a median of 2 courses of SGI-110 (range, 1-20). LINE-1 demethylation data at the 2 highest dose levels which were well tolerated and evaluated for all 3 regimens (60 and 90 mg/m2) are shown in the figure below. The Dailyx5 regimen demonstrated the most potent average LINE-1 demethylation, while the Twice Weeklyx3 achieved the most prolonged LINE-1 demethylation. The least potent demethylation was seen with the Weeklyx3 regimen. There was no additional demethylation at the 90 mg/m2 dose compared to 60 mg/m2in all 3 regimens. Responses were reported according to the IWG Criteria 2006 (MDS)/2003 (AML). Complete remissions were observed in 5 AML patients (2CRs, 1CRp, and 2CRi). Clinical responses (2 mCR and 3 HI-E, 1 HI-N, 1 HI-P) were observed in 6 MDS patients, all of whom had been previously treated with HMA. All AML responses and both mCR in MDS patients achieved ≥10% LINE-1 demethylation. Safety is reported based on Adverse Events (AEs) as graded by the CTCAE v4 criteria. Across regimens, the Twice Weeklyx3 demonstrated an increased number of related AEs compared to the other regimens. The most commonly reported related AEs ≥ 10% in the Dailyx5 regimen (injection site pain, thrombocytopenia, neutropenia, anemia, fatigue), Weeklyx3 regimen (injection site pain and diarrhea), and Twice Weeklyx3 regimen (injection site pain, injection site reaction, fatigue, dizziness, febrile neutropenia, neutropenia, anemia, and thrombocytopenia). Conclusions SQ SGI-110 is a potent HMA using all 3 regimens evaluated. The most potent hypomethylation was achieved with Dailyx5 dosing and the most prolonged hypomethylation was achieved using the Twice Weeklyx3 regimen. All 3 regimens were well tolerated. Clinical responses were observed in heavily pretreated patients, including those with prior HMA exposure. These results support the ongoing Phase 2 expansion study investigating the Dailyx5 dosing schedule in patients with MDS and AML who are either HMA treatment naïve or previously treated with HMAs. Disclosures: Roboz: Astex Pharmaceuticals, Inc.: Honoraria, Research Funding. Issa:Astex Pharmaceuticals Inc.: Honoraria, Research Funding. Rizzieri:Astex Pharmaceuticals, Inc.: Research Funding. Stock:Astex Pharmaceuticals, Inc.: Research Funding. O'Connell:Astex Pharmaceuticals, Inc.: Research Funding. Yee:Astex Pharmaceuticals, Inc.: Research Funding. Tibes:Astex Pharmaceuticals, Inc.: Research Funding. Griffiths:Astex Pharmaceuticals, Inc.: Research Funding. Walsh:Astex Pharmaceuticals, Inc.: Research Funding. Feldman:Astex Pharmaceuticals, Inc.: Research Funding. Ritchie:Astex Pharmaceuticals, Inc.: Research Funding. Rao:Astex Pharmaceuticals, Inc.: Research Funding. Larson:Astex Pharmaceuticals, Inc.: Research Funding. Garcia-Manero:Astex Pharmaceuticals, Inc.: Research Funding. Ravandi:Astex Pharmaceuticals, Inc.: Research Funding. Jabbour:Astex Pharmaceuticals, Inc.: Research Funding. Cortes:Astex Pharmaceuticals, Inc.: Research Funding. Schimmer:Astex Pharmaceuticals, Inc.: Research Funding. Mesa:Astex Pharmaceuticals, Inc.: Research Funding. Blum:Astex Pharmaceuticals, Inc.: Research Funding. Chung:Astex Pharmaceuticals Inc.: Research Funding. Naim:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals Inc.: Employment. Hao:Astex Pharmaceuticals Inc.: Employment. Choy:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals Inc.: Employment. Kantarjian:Astex Pharmaceuticals, Inc.: Research Funding.

Abstract Background: MDSs are clonal hematopoietic stem cell malignancies characterized by cytopenias resulting from ineffective hematopoiesis. A phase 2 study of lenalidomide (MDS-002) demonstrated hematological improvement in patients with MDS without an associated deletion 5q cytogenetic abnormality (List AF, et al. Haematologica2006;91[suppl1]:379[abst 1032]). We now report multicenter results after 〉2 yrs follow-up. Methods: A total of 214 pts with transfusion-dependent anemia were categorized into the following IPSS MDS risk groups after central review of bone marrow morphology, karyotype, and peripheral blood findings: Low/Int-1 (168 [78%]); Int-2/High (8 [4%]); and unclassified (38 [18%]). Patients were unclassified for missing or inadequate marrow studies for central review (morphology [29] or cytogenetic [7]) or other diagnoses (AML [1], atypical CML [1]). Patients were evaluated for frequency and duration of red blood cell transfusion independence (RBC-TI) (IWG criteria), hemoglobin (Hgb) response, and safety. The starting dose of lenalidomide was 10 mg (daily or daily × 3 wks q28d cycle). Results: Overall, 56 (26%) of 214 enrolled patients achieved RBC-TI. Median time to RBC-TI was 5 wks, median duration of RBC-TI response was 41.0 wks (range, 8.0–136.4), and median Hgb increase achieved during RBC-TI was 3.2 g/dL (range, 1.0–9.8). An additional 36 patients experienced a ≥ 50% reduction in RBC transfusions (overall hematological improvement in 92 [43%] patients). Overall, 47 (22%) patients had an abnormal karyotype at baseline and 9 (19%) patients achieved a cytogenetic response (4 complete). The most common drug-related grade 3/4 adverse events (AEs) were neutropenia and thrombocytopenia (25% and 20%, respectively). Deep vein thrombosis occurred in only 2 (1%) patients. The duration of RBC-TI was ≥ 52 weeks in 21 (38%) patients. Among these 21 patients, 14 (67%) did not require a lenalidomide dose reduction during the first 52 weeks of treatment. Analyses of response variables will be presented. Dose-limiting neutropenia/thrombocytopenia was not reported after 52 weeks. The most commonly reported AEs after 52 weeks were mild-moderate diarrhea and fatigue (38% and 29%, respectively). Conclusion: Lenalidomide is an active, well-tolerated treatment in MDS patients with transfusion-dependent anemia that is not associated with a deletion 5q abnormality. The rate of erythroid hematologic improvement and duration of RBC-TI is encouraging and offers a possible alternative to cytokine therapy.

Abstract Background: Myelodysplastic syndromes (MDS) are hematological disorders characterized by chronic anemia, and are often refractory to cytokine therapy. Two phase 2 studies evaluating lenalidomide in MDS (MDS-001 and MDS-003), demonstrated a high frequency of erythroid response in patients with a chromosome 5q31 deletion (List AF et al., N Eng J Med2005; 352:549–557 and List AF et al., in press). Herein we report on the durability of response with long term follow-up approaching 4 years. Methods: All enrolled subjects were evaluated for frequency and duration of red blood cell transfusion independence (RBC-TI), change in hemoglobin (Hgb), pathologic and cytogenetic response, and safety. Results: Ten 5q31- patients achieved a cytogenetic and/or major erythroid response in MDS-001. Four of these patients have maintained a major response for at least 2 years (range 2.2 to 3.7 years). In MDS-003, 99 (67%) of 148 enrolled patients achieved RBC-TI. Of the 99 responders 83 were Low/Int-1, 3 were Int-2/High and 13 were not classified. Median increase in Hgb from baseline to maximum achieved during RBC-TI was 5.4 g/dL (range 1.1, 11.4). The estimated median duration of response was 115.9 weeks, and 52 (53%) of 99 responders remain on study with ongoing RBC-TI response as of 30 June 2006. Duration of response was at least 52 weeks for 63 (64%), 78 weeks for 52 (53%), and 104 weeks for 36 (36%) of 99 responding patients. Variables (or co-variates) associated with longer duration of TI in multivariate analysis included low baseline transfusion requirement (<4 units per 8 wks, p=0.002), 5q- syndrome (p=0.01) and low IPSS (p=0.02) classifications. Among 85 evaluable patients, major cytogenetic responses were achieved in 37 (44%) and minor responses in 24 (28%). Cytogenetic responses occurred in patients with complex karyotypes as well as those with an isolated 5q31 deletion. The frequencies of major and minor cytogenetic responses were similar among patients with and without 5q- syndrome. The most common drug-related adverse events (AE) were Grade 3/4 neutropenia and thrombocytopenia, reported in 87 (59%) and 74 (50%) of 148 patients, respectively although hematologic AEs led to study discontinuation in only 13 (9%) of patients. Pneumonia was the only serious adverse event that occurred in >10% of patients (15/148; 10%). Adverse events were manageable through supportive treatment and dose reduction. Conclusion: Lenalidomide is an effective treatment in MDS patients with an associated chromosome 5q31 deletion, with RBC-TI and major erythroid response maintained for median duration > 2 years.

Abstract Abstract 1508 Background: Tipifarnib is an orally bioavailable farnesyltransferase inhibitor with well-established antileukemic activity in a minority of unselected patients with AML. Seeking to identify patients most likely to have tipifarnib-responsive AML, we applied a PCR-based quantitative 2 gene expression signature ratio (RASGRP1:APTX), which had been tested and validated retrospectively as a predictor of response and survival in previous large studies of tipifarnib, as a molecular screening tool for selection of patients to this pilot trial. Objectives: 1) primary: to determine the complete response (CR +CRi) rate in AML patients prospectively selected for tipifarnib treatment on the basis of a 2-gene signature (RASGRP1:APTX ratio) in bone marrow aspirates. 2) secondary: to assess safety, overall survival, and immunophenotypic expression of RASGRP1 on baseline bone marrow blasts for correlation with PCR-based detection. Methods: This was a multicenter, open-label, phase 2 study. Key eligibility criteria included 1) patients with previously untreated AML, age ≥65 years and deemed unsuitable for or refusing traditional induction chemotherapy, and 2) RASGRP1: APTX ratio of ≥5.0 (measured in bone marrow aspirate) based upon qRT-PCR. Other inclusion criteria included: ECOG PS 0–2, adequate end-organ function, and WBC < 30,000/microliter. Treatment consisted of Tipifarnib 300 mg BID × 21 days, with 7 days off. Dose escalation to 600 mg BID following cycle 1 was permitted for patients who had stable disease (SD) after cycle 1. Patients who achieved CR/CRi or PR after 2 cycles were eligible to continue treatment for up to 6 cycles maximum. Results: A total of 62 patients were consented to the trial. Of these, 21 (34%) were eligible based upon the required 2-gene ratio. Assay results were reported within 72 hours for all patients. Median age was 75 years. Fourteen (67%) patients had adverse karyotype and 14 (67%) had secondary AML (including 7 patients who received prior therapy for MDS). Three patients were replaced during cycle 1, due to withdrawal of consent or early unrelated death, such that 18 patients were considered evaluable for response. Median RASGRP1:APTX was 14.8. Two patients (11%) achieved CR and 6 (33%) additional patients had both SD and achievement of ≥50% reduction in bone marrow blasts by completion of cycle 2. Two of these 6 patients also had ≥50% increase in peripheral blood neutrophils or platelets. All 8 patients with CR or SD received at least 2 cycles of therapy. There was no correlation between baseline RASGRP1:APTX ratio and response. Overall, tipifarnib was well tolerated. Early death (≤ 30 days) was observed in only 1 patient (5%). The most common therapy-related non-hematologic toxicities (mainly grade 1–2) included: anorexia (33%), nausea (33%), fatigue (28%), febrile neutropenia (23%) and diarrhea (23%). Due to the trial not meeting its primary endpoint of at least 3 CR/CRi after 2 cycles, accrual to the trial was suspended. Conclusion: Monotherapy with tipifarnib in preselected elderly patients with AML and a RASGRP1:APTX ratio of ≥5 was associated with significant antileukemic activity and good tolerance. Although the primary endpoints during the first stage of the trial were not met, this study demonstrated the ability to rapidly and efficiently execute a biomarker-driven trial in an aggressive malignancy. Given the observed antileukemic activity in this selected population, along with a favorable toxicity and bioavailability profile for chronic dosing, further study of tipifarnib with less rigid endpoints than CR/CRi is warranted. Updated survival and RASGRP1 protein expression data will also be presented. Disclosures: Off Label Use: Tipifarnib in AML. Knoblauch:Johnson & Johnson: Employment. Karkera:Johnson & Johnson: Employment.

Abstract T is a farnesyltransferase inhibitor with clinical activity in elderly adults with newly diagnosed AML who are not candidates for TCC. For adults age ≥ 65 with poor-risk AML, T 600 mg BID for 21 out of 28–63 days induced complete remissions (CR) in 14%, median duration 7.3 mos, median survival 18.3 mos (Lancet JE, et al, Blood109:1387–1394,2007). In vitro, T+E exhibits synergistic anti-AML activity. In an attempt to increase CR rates in elderly AML pts, we conducted a Phase I trial of oral T+E, with escalation of both drugs and 14 vs. 21 days of T every 28–63 days (median 31 days, range 29–50). T+E resulted in a 25% CR rate (21/84 pts), duration 2 – 26+ mos, with best rates achieved with T dose ≥ 400 mg BID for 14 days (Karp JE, et al, Blood108:130a,2006). In the context of this trial, we have conducted longitudinal laboratory studies of changes in DNA damage and apoptosis in AML marrow blasts obtained from 84 patients prior to T+E (Day 0) and on Day 8 of T+E. Blasts were enriched by Ficoll density gradient separation and fixed in 70% ethanol. Persistent, unrepaired DNA damage was quantified by flow cytometry of cells stained with antibody to phosphorylated histone H2AX (γH2AX). Apoptosis was measured by flow cytometry of propidium iodide-stained cells with sub2n DNA content as observed in cell cycle distribution. To date, we have analyzed changes in in vivo γH2AX from 10 pts (4 CR, 6 stable disease or no response, SD/NR). CR pts had a 2-fold increase (range 1.91–2.22) in DNA damage induced by Day 8 of T+E relative to Day 0 values, while patients with SD/NR had no such increase (0–1.06) in DNA damage. Similarly, the apoptotic fraction of the cell cycle distributions of CR patients increase by 2-fold (range 1.2–5.3) for Day 8 marrow blasts. In contrast, changes in apoptosis were widely divergent for SD/NR patients (range 0.2–7.0). Taken together, these preliminary studies on AML marrow blasts obtained prior to and during T+E therapy suggest a possible linkage among induction of DNA damage, apoptotic response, and clinical outcome. Full analysis of all acquired specimens is ongoing.

Abstract Abstract 414 Background: SGI-110 is a dinucleotide of decitabine (DAC) and deoxyguanosine formulated as a low volume and pharmaceutically stable SQ injection allowing more extended decitabine exposure than DAC IV infusion. The anticipated differentiated PK profile offers the potential of improved biological and clinical activity and safety over currently available HMAs. Methods: A randomized Phase 1–2 FIH Pharmacokinetics/Pharmacodynamics (PK/PD)-guided, dose-escalation study has been conducted in patients with relapsed/refractory intermediate or high-risk MDS or AML. The objective of the first stage (dose escalation) is to determine safety and tolerability and to establish the Maximum Tolerated Dose (MTD) and Biologically Effective Dose (BED). Patients were randomized to one of two SQ regimens (dailyx5 or once weeklyx3, 28-day courses). PD is evaluated by LINE-1 global DNA hypomethylation. The second stage (dose expansion) is to determine the clinical activity and safety in AML and MDS using the established BED and MTD. We report here the results of the dose escalation phase which has completed enrolment. Results: 78 patients (64 AML, 14 MDS) were enrolled in the dose escalation phase: 44 patients in the dailyx5 regimen and 34 in the weeklyx3 regimen. Median age was 69 years (range 29–86), 65% were male, and 82% had ECOG PS of 0–1. Median number of prior regimens was 3 (range 1–9), 59% of patients had prior HMA treatment (50% of AML patients, and 100% of MDS patients). Six patients are still ongoing treatment. The PK profile demonstrated efficient conversion of SGI-110 to decitabine as predicted from the SGI-110 rational design, resulting in longer decitabine exposure window (beyond 8 hrs) compared to DAC IV (3–4 hrs). At SGI-110 dose range of 60–125 mg/m2, observed mean decitabine AUCs (88–231 ng*hr/mL) reach or exceed the therapeutic range seen with 20 mg/m2 DAC IV (115 ng*hr/mL) while achieving only a small fraction of the Cmax (26–64 ng/mL vs 146 ng/mL for DAC IV). The effective half-life for decitabine after SQ SGI-110 injection appeared to be prolonged (up to 4-fold or ∼2.4 hrs) compared to DAC IV (0.58 hrs). Decitabine exposures (AUC) increased in a dose-proportional manner regardless of the regimen and no accumulation was observed. Dose-related LINE-1 hypomethylation was observed in patients treated with the daily regimen between 18 and 60 mg/m2; a plateau in maximum average hypomethylation (∼25%) was evident at higher daily doses (90-125 mg/m2) and therefore the BED for the dailyx5 schedule is established at 60 mg/m2. The 25% average hypomethylation of LINE-1 compares favorably with that observed historically after DAC IV at the dose of 20 mg/m2 dailyx5. The extent of LINE-1 hypomethylation after weeklyx3 SGI-110 was inferior as the maximum average hypomethylation plateaued at ∼8% from baseline. Starting at 36 mg/m2 daily and 60 mg/m2 weekly (44 AML, and 7 MDS patients), clinical responses were observed: 2CRs, 1CRp, and 1CRi in heavily pretreated AML patients; 1 mCR and 1 HI in MDS patients previously treated with azacitidine. All responses were in patients who achieved >10% LINE-1 hypomethylation. The most common Adverse Events (AEs), regardless of relationship to SGI-110, were diarrhea (21%), febrile neutropenia (17%), fatigue/injection site pain/nausea at 15% each. The most common drug-related AEs were injection site pain (15%), fatigue (8%), nausea (6%), and thrombocytopenia (5%). MTD was not reached with the weekly regimen up to 125 mg/m2 weeklyx3. With the daily regimen, 125 mg/m2dailyx5 resulted in 2 Dose-Limiting Toxicities (DLTs) of febrile neutropenia in 3 MDS patients (1 associated with bacteremia, and the other with sepsis and thrombocytopenia Grade 4) while none of the 9 patients with AML had DLT at that dose. Conclusions: SGI-110 is well tolerated at doses higher than BED which is established at 60 mg/m2 dailyx5 where average hypomethylation of ∼25% was achieved. MTD estimated to be 90 mg/m2 dailyx5 for MDS and 125 mg/m2dailyx5 for AML patients. SQ administration of SGI-110 achieved efficient conversion to decitabine resulting in an improved PK profile over DAC IV. Clinical responses were observed in this heavily pretreated population and they seem to correlate with the extent of LINE-1 hypomethylation. Study is currently enrolling patients in the dose-expansion Phase 2 stage. Disclosures: Kantarjian: Astex Pharmaceuticals: Research Funding. Roboz:Astex Pharmaceuticals: Research Funding. Rizzieri:Astex Pharmaceuticals: Research Funding. Stock:Astex Pharmaceuticals: Research Funding. O'Connell:Astex Pharmaceuticals: Research Funding. Griffiths:Astex Pharmaceuticals: Research Funding. Yee:Astex Pharmaceuticals: Research Funding. Tibes:Astex Pharmaceuticals: Research Funding. Garcia-Manero:Astex Pharmaceuticals: Research Funding. Ravandi:Astex Pharmaceuticals: Research Funding. Walsh:Astex Pharmaceuticals: Research Funding. Feldman:Astex Pharmaceuticals: Research Funding. Ritchie:Astex Pharmaceuticals: Research Funding. Rao:Astex Pharmaceuticals: Research Funding. Decastro:Astex Pharmaceuticals: Research Funding. Schimmer:Astex Pharmaceuticals: Research Funding. Mesa:Astex Pharmaceuticals: Research Funding. Syed:Astex Pharmaceuticals: Research Funding. Choy:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals: Employment. Taverna:Astex Pharmaceuticals: Employment. Azab:Astex Pharmaceuticals: Employment. Chung:Astex Pharmaceuticals: Research Funding. Issa:Astex Pharmaceuticals: Honoraria, Research Funding.

Abstract Tipifarnib (T) exhibits modest activity in elderly adults with newly diagnosed acute myelogenous leukemia (AML). Based on preclinical synergy, a phase 1 trial of T plus etoposide (E) yielded 25% complete remission (CR). We selected 2 comparable dose levels for a randomized phase 2 trial in 84 adults (age range, 70-90 years; median, 76 years) who were not candidates for conventional chemotherapy. Arm A (T 600 mg twice a day × 14 days, E 100 mg days 1-3 and 8-10) and arm B (T 400 mg twice a day × 14 days, E 200 mg days 1-3 and 8-10) yielded similar CR, but arm B had greater toxicity. Total CR was 25%, day 30 death rate 7%. A 2-gene signature of high RASGRP1 and low aprataxin (APTX) expression previously predicted for T response. Assays using blasts from a subset of 40 patients treated with T plus E on this study showed that AMLs with a RASGRP1/APTX ratio of more than 5.2 had a 78% CR rate and negative predictive value 87%. This ratio did not correlate with outcome in 41 patients treated with conventional chemotherapies. The next T-based clinical trials will test the ability of the 2-gene signature to enrich for T responders prospectively. This study is registered at www.clinicaltrials.gov as #NCT00602771.