Ravandi, Farhad

Abstract Abstract 2926 Background: RAS proteins are encoded by 3 proto-oncogenes (K-RAS, N-RAS, and H-RAS) and regulate the growth and differentiation of many cellular types, including the myeloid compartment. Codons 12, 13, and 61 (in N-RAS and K-RAS) have been reported to be common targets of mutations. These mutations result in constitutive activation of the RAS pathway by increasing intracellular RAS GTP levels, which result in activation of the RAS/MEK and the RAS/PI3K pathways. Its prognostic significance in MDS is yet to be clarified. Because the potential prognostic and therapeutic implications of RAS mutations in MDS, we decided to study the impact of RAS mutations in patients (pts) with MDS. Methods: Mutation analysis of KRAS and NRAS codons 12, 13, and 61 was performed by Pyrosequencing using biotinylated reverse primers. All pts referred to MD Anderson between 2000–2009 were reviewed. In addition to standard clinical characteristics, including karyotyping, mutational status of Flt3, c-Kit and JAK2 was also analyzed. Overall survival was calculated based on Kaplan-Meier. Results: Of the 1067 pts with MDS of age above 17 evaluated for RAS mutation, 43 pts (4%) were positive. Seventy nine percent of RAS mutations were of N-RAS type (codon12 (55%), codon 13 (12%), codon 61(12%)) with K-RAS 12 comprising the rest (21%). Median age was 68 years (range, 18–94) with 66% being males (703 pts). Their median white blood cell (WBC) was 3.3×109/L (range, 0.3–72.2), hemoglobin 9.8 (range, 3–17.5), and platelets 73×109/liter (range, 1–1040). Median bone marrow blast was 5% and 77 pts (7%) had leukemic transformation. More than half of the pts had RAEB or RAEB-t (44% and 9 % respectively) which translated into fewer patients in the low IPSS category (19%). The median age was 66 years (range 26–84) in the RAS mutated (muRAS) group compared to 68 in the wild type (wtRAS). WBC was higher in the muRAS group compared to wtRAS (6.8 ×109/L vs. 3.2 ×109/L, p<0.001 by Mann-Whitney median test (M-W-T)). Percent of bone marrow blasts was higher (9%) in muRAS group compared to 5% in wtRAS (p<0.001 by M-W-T). High (Int-2 and high) risk by IPSS was more frequent in muRAS 51% compared to 40% in wtRAS group (p=0.11). Leukemic transformation was 9% and 7% (p=0.61) in both muRAS and wtRAS groups respectively. RAS mutation was detected more frequently in the CMML subgroup (12/80 (15%) pts). There were no differences in terms of response to DNA methylating inhibitors (CR in 41% in muRAS versus 40% in wtRAS). ARA-C-based regimens resulted in better CR in wtRAS than muRAS (59% vs 25%); however, the size of muRAS group was too small (1 out 4 pts).There was a trend towards shorter overall survival (OS) in the muRAS group compared to wtRAS (395 vs. 500 days, p value=0.057). MuRAS RAEB (325 vs. 450 days, p= 0.13) and RAEB-t (125 vs. 375 days, p= 0.27) subgroups showed a trend towards worse OS compared to wtRAS group. There was a significant OS decrease in RCMD (150 vs. 700 day, p= 0.015). Surprisingly, muRAS CMML group showed a trend towards better OS compared to wtRAS (728 vs. 687 days, p=0.44). Additionally we analyzed patients for presence of Flt3 mutation. These were present in only 18 of the pts (4%) but none of them had also a RAS mutation. There was no c-Kit mutations found in this cohort of pts, compared to 9/37 (24%) pts tested positive for JAK2V617F. Conclusion: MuRAS occurs in 4% of pts with MDS. In the muRAS group, pts tended to have higher risk disease and risk of transformation to acute leukemia compared with wtRAS. OS tended to be worse in some subgroups in muRAS. Although the prognostic impact of RAS mutations in MDS appears to be limited, mutations could be used to develop targeted therapeutic interventions. Disclosures: No relevant conflicts of interest to declare.

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: The study of rare diseases is limited by the uncommon nature of the conditions as well as the widely dispersed patient populations. Current rare disease registries such as the National Organization of Rare Diseases utilize centralized platforms for data collection; however because of their broad nature, these do not always capture unique, disease specific elements. Hairy Cell Leukemia (HCL) is a rare leukemia globally with approximately 900 new cases diagnosed in the US each year. The HCL Foundation undertook creation of a Patient Data Registry that collects data from multiple HCL Centers of Excellence (COE) around the globe to better understand the complications, treatment outcomes, disease subtypes, comorbid conditions, epidemiology, and quality of life of patients with HCL. METHODS: Investigators at The Ohio State University Department of Biomedical Informatics and Division of Hematology in collaboration with the HCL Foundation developed a Patient Data Registry (PDR) for the longitudinal capture of high quality research data. This system differs from other registries in that it uses a federated( rather than centralized) architecture, wherein data is queried and integrated in an on-demand manner from local registry databases at each participating site. Further, the data collected for use in the registry combines both automated exports from existing electronic health records (EHRs) as well as additional data entered via a set of web-based forms. All manually entered data comes from source documents, and data provenance spanning electronic and manually entered data is maintained via multiple technical measures. Patients may be enrolled at HCL COE, or, if they do not have access to a COE they may enroll via a web-based portal (www.hairycellleukemia.org). At this time due to regulatory requirements the web-based portal is available to US patients only. All data are de-identified (see Figure 1: De-Identification Workflow) which reduces regulatory burden and increases opportunities for data access and re-use. End users have access to data via a project-specific query portal. RESULTS: The Patient Data Registry has been deployed at The Ohio State University, Royal Marsden Hospital, and MD Anderson Cancer Center, and is undergoing deployment at the University of Rochester. Up to 25 international HCL COE may participate. In addition, US patients are actively entering the registry via the web-based portal. To date, 227 patients have been consented to the registry with 119 of these being via the web-based entry point. CONCLUSION: We created an international and web-based patient data registry which will enable researchers to study outcomes in HCL in ways not previously possible given the rarity of the disease. This work was made possible by research funding from the Hairy Cell Leukemia Foundation. Figure De-Identification Workflow Figure. De-Identification Workflow Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lele:Hairy Cell Leukemia Foundation: Research Funding. Burger:Pharmacyclics: Research Funding. Delgado:Gilead: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding. Montserrat:Morphosys: Other: Expert Testimony; Vivia Biotech: Equity Ownership; Gilead: Consultancy, Other: Expert Testimony; Pharmacyclics: Consultancy; Janssen: Honoraria, Other: travel, accommodations, expenses. Parikh:Pharmacyclics: Honoraria, Research Funding. Park:Genentech/Roche: Research Funding; Amgen: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tam:janssen: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heckler:Hairy Cell Leukemia Foundation: Research Funding. Payne:Hairy Cell Leukemia Foundation: Research Funding.

Abstract Abstract 788 FLT3 mutations are common in AML and are associated with poor prognosis. Lestaurtinib is a multi-targeted kinase inhibitor with potent activity against FLT3. In an attempt to definitively establish whether or not there is clinical benefit for FLT3 inhibition in the relapse setting, we conducted a randomized trial of chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Patients were randomized to receive either chemotherapy alone, consisting of mitoxantrone, etoposide, and cytarabine (MEC) or high-dose cytarabine (HiDAc) depending on the duration of CR1) or chemotherapy followed by 80 mg lestaurtinib orally BID. Patients on the chemotherapy only arm were eligible for crossover if they were refractory to therapy. Patients on the lestaurtinib arm received the drug for up to 112 days on study (they could continue to receive the drug through a separate extension protocol). The primary objective was complete remission (CR/CRp). Secondary objectives included overall survival (OS), safety, and tolerability. From January 2004 through December 2008, 224 patients at 52 different centers were enrolled and randomized, with 220 patients actually receiving therapy. Blood samples from patients on the lestaurtinib arm were obtained at baseline, on Day 15, and on Day 42 for pK studies and for determination of in vivo FLT3 inhibition and measurement of plasma FLT3 ligand (FL) and alpha-1 acid glycoprotein (AGP) levels. The median age for all patients enrolled was 55 years (53.5 in the control arm, 58.5 in the lestaurtinib arm), with 88% having FLT3/ITD mutations, 8% having D835 mutations, and 4% having both. The duration of CR1 was less than 6 months in 47% of patients in each arm. On the lestaurtinib arm, 107 patients received at least 1 week of lestaurtinib (mean 60.1 days, range 8-418), with 17 of these patients receiving drug on the extension protocol. On the chemotherapy only arm, 7 patients crossed over to receive lestaurtinib, and 31 patients went on to receive lestaurtinib on the extension protocol after outcome evaluation. Lestaurtinib was generally well tolerated following chemotherapy, with 104 Grade 3/4 adverse events in the lestaurtinib arm versus 99 in the control arm. There were 61 serious adverse events in the lestaurtinib arm versus 49 in the control arm. Early death (by Day 42) occurred in 22 lestaurtinib patients (2 progressive leukemia, 14 infectious, 6 organ failure) and16 control patients (6 progressive leukemia, 5 infectious, 5 organ failure). By intention to treat analysis, there were 29 CR/CRp in the lestaurtinib arm and 23 in the control arm (26% versus 21%; p = 0.35), with no difference in OS (4.73 months versus 4.57 months) between the two arms. Blood samples from 79 of the 107 lestaurtinib-treated patients obtained on Day 15 were analyzed for FLT3 inhibitory activity (plasma inhibitory activity [PIA] assay), as well as FLT3 ligand (FL), lestaurtinib, and AGP concentrations. Mean lestaurtinib plasma concentration was 12 uM at Day 15 and fell to 7.5 uM on Day 42. Mean lestaurtinib concentration at Day 15 was 13.3 uM in patients achieving CR/CRp and 11.5uM in non-responders. A target of >85% inhibition of FLT3 maintained at trough (pre-dose) was defined from previous studies. Of the 79 patients tested, 46 (58%) achieved this degree of FLT3 inhibition on Day 15. FL concentrations rose from baseline (15.6 pg/mL) to Day 15 (1148 pg/mL), and AGP concentrations rose by an average of 52% over the same period, both of which may have reduced the degree of FLT3 inhibition. Of the 46 patients with target FLT3 inhibition on Day 15, 18 (39%) achieved CR/CRp, while only 3 (9%) of the 32 patients with below target FLT3 inhibition achieved CR/CRp. Thus, in patients with FLT3 mutant AML at first relapse, pharmacokinetic factors and possible physiologic factors (FL and AGP) limit lestaurtinib's ability to effectively inhibit FLT3. FLT3 inhibition by lestaurtinib, when achieved, correlates with better CR rates, but in this trial that benefit was negated by a poor CR rate in those patients for whom the drug did not reach the target level of FLT3 inhibition. Overall, lestaurtinib treatment following re-induction chemotherapy failed to increase response rates or prolong survival of patients with FLT3 mutant AML in first relapse. Disclosures: Levis: Cephalon: Clinical Advisory Board member. Ravandi:Cephalon: Honoraria, Member, clinical advisory board, Research Funding. Erba:Cephalon: Research Funding, Speakers Bureau. Baccarani:Novartis Pharma, Bristol Myers Squibb, Merck Sharp & Dome, Pfizer: Consultancy, Speakers Bureau. Stone:Cephalon: ad hoc consultancy; Novartis: Research Funding, ad hoc consultancy. Advani:Cephalon: Research Funding. Douer:Cephalon: Honoraria, Research Funding, Speakers Bureau. Litzow:Cephalon: Research Funding. Tremmel:Cephalon: Employment, Equity Ownership. Bensen-Kennedy:cephalon: Employment. Smith:Cephalon: Research Funding.

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.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

e18521 Background: The FDA-approved drug trabectedin is a DNA minor groove binder (MGB) with activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB, with activity against myeloid leukemia cells. A phase I clinical trial was initiated to determine recommended doses in MDS/AML. Further assessment of its safety, tolerability, and pharmacogenetics were studied. Methods: In total, 42 patients with relapsed/refractory MDS/AML received lurbinectedin, using a 3+3 study design. It was administered as a 1-hour IV infusion first at 3.5, 5, 6, and 7mg per dose on days 1 and 8. Subsequently, it was administered on days 1, 2, and 3, using 1, 1.5, 2, or 3mg per dose per patient. Results: Three patients had dose-limiting toxicities (DLTs), which were rhabdomyolysis (up to gr 4), hyperbilirubinemia (gr 3), and oral herpes (gr 3). All DLTs occurred in the 6 and 7mg cohorts. Adverse events included febrile neutropenia/infections (n = 3), GI (n = 6) and pulmonary (n = 2) toxicity, hyperhidrosis (n = 1), and QT prolongation (n = 1). Overall, 33 of 42 patients (79%) had reduction of blasts in peripheral blood (PB) or bone marrow (BM) at nadir, including 23 (55%) with > 50% reduction in PB blasts alone (n = 18) or both BM and PB blasts (n = 5). One patient had PR, 2 patients had morphologic leukemia-free survival, and most (n = 30) were discontinued for progressive disease. Early deaths occurred from disease-related causes, not attributable to lurbinectedin. Thirty-two patients treated at MD Anderson were analyzed for clinical characteristics and responses. Notably, among patients with follow-up bone marrow biopsy, those with a cytogenetic abnormality at chromosome 11q21-23 had significantly greater bone marrow blast reduction than those without such abnormality (change in percentage blasts: -31±14% [n = 4] vs. 8±8% [n = 16], respectively; P= 0.04). Conclusions: Lurbinectedin is generally safe and tolerated at dose levels tested. While no sustained remissions > 3 cycles were observed in these highest-risk patients, single-agent lurbinectedin was transiently leukemia suppressive for some patients, including some with abnormal chr11q or TP53 mutation. Rational combinations and situational uses of lurbinectedin are under consideration. Clinical trial information: NCT01314599.