Kura Oncology Research Articles

Rigosertib Oral in Transfusion Dependent Lower Risk Myelodysplastic Syndromes (LR-MDS): Optimization of Dose and Rate of Transfusion Independence (TI) or Transfusion Reduction (TR) in a Single-Arm Phase 2 Study

Background:LR-MDS patients have limited treatment options and a large number are transfusion dependent (Raza A, Expert Opinion 2016, 4:9). Erythropoiesis stimulating agents (ESA) are the first line of therapy for LR-MDS patients, but the overall response rate remains low. Thus, novel strategies with the goal of red blood cell (RBC) transfusion reduction (TR) and independence (TI) are required. Rigosertib, a small molecule inhibitor of RAS effector pathways (Athuluri-Divakar SK, Cell 2016;165:643) is under investigation in MDS. The absolute bioavailability of oral rigosertib is about 35% (Komrokji, BJH 2013; 162:517). Here we expand an earlier report (Raza A, ASH 2013 #2745) on rigosertib oral in LR-MDS with updates on dose optimization on the frequency of TI or TR.Methods:Rigosertib oral was tested in this phase 2 study in LR (intermediate-1 or low risk per IPSS classification) transfusion-dependent MDS patients. Fifty-four (65.9%) patients had received ESA. Rigosertib was administered to RBC transfusion-dependent patients; defined as requiring a minimum of 4 packed red blood cell (PRBC) units over 8 weeks, in the cohorts shown in see Table below. Patients were eligible for efficacy analysis if they received a minimum of 8 weeks of rigosertib in their assigned dosing cohort. Erythrocyte stimulating agents (ESAs) were allowed on study. TI is defined as no PRBC transfusions over a period of 8 sequential weeks; TR a reduction in 4 or more RBC units over a period of 8 sequential weeks.Results:Eighty-two patients with a median age of 70 years (range 54-90) were enrolled between May 2012 and February 2015, at 5clinical sites, and received a median of 5.4 months (range 0.1-28.8) of oral rigosertib. Of the 82 enrolled patients, 9 patients were treated with 560 mg BID continuously, 7 patients treated with 560 mg in the AM and 280 mg in the PM continuously, 35 patients treated with 560mg BID intermittently, 31 patients treated with 560mg in the AM and 280mg in the PM intermittently. Sixty patients were treated with ESA and oral rigosertib while on study. An unusual adverse event (AE) (urinary events) was identified as related to dosing. Continuous rigosertib dosing cohorts were closed early due to higher urinary adverse events (AEs) or less efficacy with the lower dose of rigosertib.EfficacyOf the 82 patients, 66 patients received intermittent dosing for at least 8 consecutive weeks; and 20 of 62 evaluable patients (32%) achieved TI lasting 8 to 85+ weeks; with a median of 18 weeks. The highest rate of TI (44%) was observed in the 560 mg BID intermittent cohort: 15 of 34 eligible patients achieved TI lasting 8 to 85+ weeks; with a median of 18 weeks (TABLE). Ninty-three percent (93%) of these 15 patients received rigosertib with continued ESA.SafetyDue to urinary AEs continuous 560 mg BID dosing is no longer being studied. For all intermittent patients (n=66); the most frequent treatment emergent adverse events observed were urinary with pollakiuria (42.4%), fatigue and micturition urgency (33.3%), urinary tract pain (28.8%), hematuria and dysuria (24.2%).In the 560 mg BID intermittent group, 71.4% of all patients experienced urinary AE, the most frequent being pollakiuria (51.4%), micturition urgency (37.1%), and dysuria, hematuria, and urinary tract pain (34.3%); and fatigue (42.9%). Grade 3 or greater hematuria was observed in 11.4% of these patients and dysuria and urinary tract pain in 5.7%. Several strategies were investigated to ameliorate or manage the urinary AEs.Notably, no significant treatment emergent myelosuppression, or other notable AEs were evident in these patients.Conclusions:Oral rigosertib treatment resulted in TR & TI. Patients administered rigosertib for 2 out of 3 weeks at a dose of 560 mg BID (1120 mg over 24 hrs) achieved an impressive TI rate of 44% (15/34). Based on the rate of TI, and the observed urinary AEs, the risk benefit profile of oral intermittent dosing is favorable. Oral rigosertib at a total dose of 1120 mg over 24 hrs administered intermittently in HR-MDS pts in combination with azacitidine is now being studied; with novel strategies employed to continue to minimize the unusual urinary AEs. [Display omitted] DisclosuresRaza:Kura Oncology: Research Funding; Celgene Inc.: Research Funding; Syros Pharmaceuticals: Research Funding; Janssen R&D: Research Funding; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Onconova Therapeutics: Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals: Consultancy; Amgen: Consultancy; Clinipace: Consultancy; Baxalta: Consultancy. Ali:Kura Oncology: Consultancy; Onconova Therapeutics: Consultancy. Fruchtman:Onconova Therapeutics, Inc.: Employment. Petrone:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Heaney:Novartis: Consultancy; Onconova Therapeutics: Research Funding.

Early Results from a Biomarker-Directed Phase 2 Trial of Sy-1425 in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Demonstrate DHRS3 Induction and Myeloid Differentiation Following Sy-1425 Treatment

Early Results from a Biomarker-Directed Phase 2 Trial of Sy-1425 in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Demonstrate DHRS3 Induction and Myeloid Differentiation Following Sy-1425 Treatment

A Phase 2 Study of Actinium-225 (225Ac)-Lintuzumab in Older Patients with Previously Untreated Acute Myeloid Leukemia (AML) Unfit for Intensive Chemotherapy

A Phase 2 Study of Actinium-225 (225Ac)-Lintuzumab in Older Patients with Previously Untreated Acute Myeloid Leukemia (AML) Unfit for Intensive Chemotherapy

Clinical Significance of PD-1 and PD-L1 Expression and Ongoing Interaction in the Tumor Microenvironment in Diffuse Large B Cell Lymphoma (DLBCL) Treated with R-CHOP

Background: PD-1 blockade has demonstrated antitumor activity in diffuse large B-cell lymphoma (DLBCL). In order to select patients who are more likely to respond to PD-1 blockade, predictive biomarkers are being intensively pursued. PD-1 and PD-L1 expression in DLBCL treated with R-CHOP as standard-of-care has been examined in several studies. However, only overall PD-1+ cells but not T-cell specific PD-1 expression have been quantitated, and results of the prognostic significance of PD-L1 expression have been inconsistent in DLBCL patients. Whether ongoing PD-1/PD-L1 interaction in tumors contributes to the adverse prognostic effect of PD-1 and PD-L1 expression is unknown.Patients and Methods: Tissue microarray (TMA) sections ofdiagnostic samples from 414 patients with de novo DLBCL treated with R-CHOP were fluorescently stained with CD3 (T cell marker), PD-1, and PD-L1. Positive cells and PD-1/PD-L1 interaction were quantitatively assessed by the Automated Quantitative Analysis (AQUA) algorithms. To characterize PD-1/PD-L1 expression in each sample, CD3+, PD-1+, PD-L1+, and PD-1+CD3+ (double positive, i.e., PD-1+ T) cell numbers were divided by total nucleated cells (DAPI+) in the representative tumor areas. Ongoing PD-1/PD-L1 interactions were evaluated by the proximity of PD-1+ T cells to the PD-L1+ compartments and proportion of PD-1+ T cells co-localized with PD-L1, generating an interaction score for each sample. Biomarker expression and interaction scores were correlated with patient survival.Results: CD3+, PD-1+, PD-L1+, and PD-1+CD3+ cells were identified in 90%, 30%, 53%, and 18% of the cohort, respectively. The mean percentages of CD3+, PD-1+, PD-L1+, and PD-1+CD3+ cells in DLBCL tissues were 12.1%, 0.44%, 3.6%, and 0.19%, respectively. Activated B-cell-like DLBCL had a significantly higher mean percentage of PD-L1+ cells, but not PD-1+CD3+ cells, compared to germinal center B-cell-like DLBCL (p=0.0012). Three prognostic tiers were identified. Firstly, absence to very low percentage (0-3.5%) of tumor-infiltrating CD3+ T cells in the tissues was associated with poorer overall survival (OS) of DLBCL patients (p=0.028). CD3high DLBCL (>3.5% of all cells were CD3+) was associated with significantly higher percentages of PD-L1+ and PD-1+ cells (p<0.0001 and p=0.005, respectively). Secondly, in CD3high DLBCL, presence of PD-1+ T cells correlated with significantly poorer OS and progression-free survival (PFS) of patients (p=0.028 and p=0.0099, respectively). In contrast, presence/absence of PD-1+ non-T cells was not prognostic. Presence of PD-1+ T cells in CD3high DLBCL was associated with a higher mean percentage of PD-L1+ cells (p=0.019). However, PD-1/PD-L1 interaction scores did not add to the prognostic effect. This may suggest that phenotype of PD-1/PD-L1 interaction is not a biomarker to specify the immunosuppressive role of the PD-1/PD-L1 axis. Lastly, in CD3high DLBCL cases with PD-1−negative T cells, PD-L1 positivity correlated with significantly poorer OS and PFS of patients (p=0.0034 and p=0.0059, respectively), although PD-L1+ was not associated with non-T PD-1 expression either, suggesting PD-1−independent function of PD-L1. In the overall cohort, presence of PD-1+ T cells was associated with a trend of poorer PFS (p=0.079), whereas PD-L1 expression was not prognostic.Conclusions: PD-1 expression in T cells and lack of tumor-infiltrating CD3+ T cells are associated with significantly poorer survival of DLBCL patients. In addition, our data suggest that PD-1 can be a prognostic marker independent of PD-1/PD-L1 co-localization, and that PD-L1 has other PD-1-independent inhibitory functions. These results demonstrate the importance of both T-cell influx and antitumor function in prolonging the survival of DLBCL patients, and provide rationales for PD-1 blockade and immunotherapies activating T cell-mediated immune responses in DLBCL. DisclosuresTran:Genoptix, Inc: Employment. Adams:Navigate BioPhama Services, Inc: Employment. Roscoe:Navigate BioPhama Services, Inc: Employment. Hsi:Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Abbvie: Research Funding; Eli Lilly and Co.: Research Funding; Cellerant Therapeutics: Research Funding. Piris:Kura Oncology: Research Funding. Winter:Glaxo-Smith-Kline: Research Funding; Merck: Research Funding. Vaupel:Genoptix Laboratory: Employment. Dakappagari:Genoptix, Inc: Employment.

Activation Levels of b-Catenin Signaling in Osteoblasts Define a Threshold for the Development of Myeloid Neoplasia of Variable Severity

A growing body of evidence indicates that osteoblasts have a direct pathogenetic role in the development of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) and transformation of MDS to AML. Models of osteoblast-induced MDS or AML (OIAML) include b-catenin activation in osteoblasts inducing AML in mice and seen in more than 30% of MDS and AML patients; deletion of Dicer1 in osteoblast progenitors leading to MDS in mice; Noonan syndrome mutation (PTPN11) in stromal cells driving MPN in mice; and Schwachman-Diamond syndrome mutation in stromal cells driving MDS in mice and predicting AML progression in patients. To further understand the mechanism of OIAML we examined whether a defined threshold of AML-inducing signal by osteoblasts is required for disease development. For this purpose we constitutively activated b-catenin in osteoblasts using three different lines of 2.3Col1 a 1-Cre transgenic mice characterized by different recombination efficiencies in bone. Line 1, in which recombination efficiency was 80%. Line 2 was the same original line in which after several inter-breedings we detected a reduction in recombination efficiency to 20%. Line3, which has 75% recombination efficiency. Activation of b-catenin in osteoblasts using Line 1, led to the development of MDS which rapidly transformed to full-blown AML characterized by multi-organ infiltration with myeloid blasts, hematopoietic deregulation and lethality by 6 weeks of age. In contrast, activation of b-catenin in osteoblasts using Line 2 did not lead to AML development. Mice remained healthy and survived until at least 10 months of age, the entire time they were observed. Activation of b-catenin in osteoblasts using Line 3 led to anemia, with the appearance of myeloid blasts in the blood, marrow and spleen and segmented neutrophils in blood. In addition to what was observed with Line 1, Pelger Huet neutrophils and Howell-Jolly bodies were detected in the blood. The latter are RBCs with inclusions of nuclear chromatin remnants (damaged chromosome fragments) indicating genomic instability and a dysfunctional spleen, unable to clear them from the circulation, due to dense infiltration with blasts and megakaryocytes. A spectrum of atypical immature monocytes with abundant pale blue agranular cytoplasm with vacuoles were observed in the blood. Taken together these features resemble characteristics of human MDS/CMML. Mice die between 4 and 14 weeks of age, when they undergo “blast crisis” indicating transformation to AML. To examine whether and how these observations relate to the human disease, we compared the levels of b-catenin activation in osteoblasts (calculated as a function % osteoblasts (Lin-/CD34-/RUNX2+ cells) expressing activated b-catenin) with the different MDS diseases subtypes as those are defined by the 2008 World Health Organization (WHO) classification system. We found that increased levels of b-catenin activation in osteoblasts correlate with the severity of the MDS type and with conversion to AML. Collectively, these observations suggest that a minimal activation level of a key leukemogenic signal from the stroma, is required to initiate cancer development, and provides mechanistic insight into the formation and progression of preleukemic stem cells in AML and the transformation of MDS to AML. DisclosuresRaza:Onconova Therapeutics: Research Funding, Speakers Bureau; Kura Oncology: Research Funding; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Janssen R&D: Research Funding; Celgene Inc.: Research Funding; Syros Pharmaceuticals: Research Funding.

Efficacy and Safety of Imetelstat in RBC Transfusion-Dependent (TD) IPSS Low/Int-1 MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agents (ESA) (IMerge)

Background: There are limited treatment options for anemic patients with lower-risk MDS who are relapsed after or are refractory to ESA. Imetelstat is a novel, first-in-class telomerase inhibitor that targets cells with short telomere lengths and highly active telomerase, and has clinical activity in myeloid malignancies (Cancer Res 2014;4:362; NEJM 2015;373:920; NEJM 2015;373:908; BJC 2016;6:e405). Targeting MDS clones with imetelstat may improve outcomes including anemia in MDS patients relapsed/refractory to ESA. We explored the safety and efficacy of imetelstat in RBC TD patients with IPSS Low or Intermediate-1 (Int-1) risk MDS relapsed/refractory to ESA.Methods: IMerge is an ongoing 2-part, global, multicenter study in TD patients (planned enrollment 200) with Low or Int-1 IPSS risk MDS relapsed/refractory to ESAs and with transfusion requirement of ≥4 units over 8 weeks prior to study entry. ESA-naïve patients with sEPO >500 mU/mL are also eligible. Part 1 is an open-label, single-arm study assessing the efficacy and safety of imetelstat administered IV every 4 weeks at a dose of 7.5 mg/kg. Part 2 is a double-blind, randomized design comparing the efficacy of imetelstat to placebo. The primary endpoint is the rate of RBC transfusion-independence (TI) lasting ≥8 weeks. Key secondary endpoints include safety, rate of ≥24-week TI, time to and duration of TI, and hematologic improvement (HI) rate. Here we report findings from the 32 patients enrolled in Part 1 with a median follow up of 48 weeks.Results: 29 (91%) patients had ECOG 0-1, median age was 68.5 years. 59% of patients were IPSS Low and 41% Int-1. 13 patients (43%) had sEPO>500 mU/mL. 34% had a cytogenetic abnormality, including 22% with del(5q). Prior treatments for MDS included ESAs (88%), lenalidomide (38%), and decitabine or azacitidine (HMAs) (25%); 56% of patients were both lenalidomide and HMA naïve. Baseline median RBC transfusion burden was 6 units per 8 weeks (range: 4-14). As of May 2017, RBC-TI ≥8-week was achieved in 34% of patients. Median time from treatment initiation to onset of TI was 8 weeks with a median duration of TI of 19 weeks, while 16% of patients achieved ≥24-week TI. 63% of patients achieved erythroid HI; transient platelet improvement was reported for one patient. Of the 13 lenalidomide and HMA naïve patients without del(5q), 54% achieved ≥8-week TI, 31% had ≥ 24-week TI and 69% achieved erythroid HI. TI response was 35% (6/17) and 38% (5/13) in patients with sEPO level ≤500 mU/L and >500 mU/L, respectively. The most frequently reported adverse events were cytopenias, including grade ≥3 and 4 neutropenia in 66% and 41% of patients, respectively and grade ≥3 and 4 thrombocytopenia in 50% and 19% of patients, respectively. Dose reductions or cycle delays due to adverse events were required for 59% of patients. One patient experienced neutropenic fever and two patients had grade 3 thrombocytopenia concurrent with grade 1 bleeding events both considered related to imetelstat; all recovered without sequelae. 28 patients (88%) had reversible LFT elevations by at least one grade; 4 of these were by 2 grades. Reversible grade 3 elevations were reported in 3 patients.Conclusions: In IPSS Low/Int-1 RBC transfusion dependent MDS patients relapsed/refractory to ESA, TI was observed in 34% and erythroid HI in 63% with imetelstat therapy. TI response appeared to be independent of sEPO level. Reversible cytopenias were the most frequent adverse events, which were generally manageable with dose reduction or delays. Elevated LFTS were reversible. Patients who were naïve to lenalidomide and HMAs and who lacked del(5q) had a higher rate of durable TI (54%) than other groups, which should be further explored. DisclosuresFenaux:Novartis: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Raza:Kura Oncology: Research Funding; Novartis: Speakers Bureau; Celgene Inc.: Research Funding; Genoptix: Speakers Bureau; Janssen R&D: Research Funding; Onconova Therapeutics: Research Funding, Speakers Bureau; Syros Pharmaceuticals: Research Funding. Platzbecker:Novartis: Consultancy, Research Funding; Acceleron: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Santini:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Celgene: Honoraria, Research Funding; Novartis: Honoraria. Samarina:Janssen: Research Funding. Van Eygen:Janssen: Consultancy, Honoraria, Research Funding. Sherman:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Varsos:Janssen: Employment, Equity Ownership. Rose:Janssen: Employment, Equity Ownership. Rizo:Janssen: Employment, Equity Ownership. Steensma:Pfizer: Consultancy; Takeda: Consultancy; H3 Biosciences: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Equity Ownership; Onconova: Consultancy; Celgene: Consultancy.

Evaluation of the Impact of Minimal Residual Disease, FLT3 Allelic Ratio, and FLT3 Mutation Status on Overall Survival in FLT3 Mutation-Positive Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) in the Chrysalis Phase 1/2 Study

Evaluation of the Impact of Minimal Residual Disease, FLT3 Allelic Ratio, and FLT3 Mutation Status on Overall Survival in FLT3 Mutation-Positive Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) in the Chrysalis Phase 1/2 Study

Umbralisib/TGR-1202 As a Novel Dual PI3K/CK1 Inhibitor Has a Unique Therapeutic Role in Silencing Oncogenes in Aggressive Lymphomas

Introduction: A number of oncogenes have been shown to promote the pathogenesis and correlate with poor survival in aggressive lymphoma. For example, deregulation of C-MYC is prevalent in diffuse large B cell lymphoma (DLBCL), chromosome translocations involving C-MYC and BCL2 define “double hit lymphoma” (DHL), and chromosome translocation involving CCND1 is pathognomonic for mantle cell lymphoma (MCL). Despite impressive progress being made in the treatment of these aggressive lymphomas, the treatment options for patients with relapsed aggressive lymphoma, especially DHL, remain inadequate. Interestingly, translation of C-MYC, BCL2, CCND1, and a number of other oncogenes is highly sensitive to inhibition of the eukaryotic translation initiation factor 4F (eIF4F) (Manier et al., 2017; Wolfe et al., 2014), which is comprised of the eIF4E, eIF4A, and eIF4G subunits. However, inhibitors of eIF4F are currently not available for the clinic. eIF4F is negatively regulated by the eIF4E binding protein 1 (4E-BP1), which in the hypo-phosphorylated form sequesters eIF4E (Haghighat et al., 1995). To allow for robust initiation of translation in cancer cells 4E-BP1 is hyper-phosphorylated by upstream signals, such as mechanistic target of rapamycin (mTOR). Our recent results indicate that casein kinase 1 epsilon (CK1ε) positively regulate translation via phosphorylating4E-BP1 (Deng et al., 2016). There may be additional poorly understood signals regulating 4E-BP1. Although no CK1ε inhibitor has been developed for the clinic, we recently discovered that the PI3Kδ inhibitor umbralisib/TGR-1202 acts additionally to inhibit CK1ε. Given that TGR-1202 has demonstrated a favorable safety profile in clinical trials and is capable of targeting both PI3Kδ and CK1ε, the drug may be particularly valuable for the silencing of oncogenes in aggressive lymphoma. Our hypothesis is the following: If hyper-phosphorylation of 4E-BP1 serves as a nexus for upregulating oncogene translation, then co-targeting signals phosphorylating 4E-BP1, such as CK1ε and mTOR, may potently and synergistically silence oncogenes in aggressive lymphomas.Materials and Methods: Cytotoxicity was studied in lymphoma cell lines and using Cell TiterGlo (Promega®). Screen of drug synergy was performed between pairs of TGR-1202, mTOR inhibitors, proteasome inhibitors, and CK1 inhibitors. The Bliss additivism model was used to determine the expected inhibition of cell growth and the excess over Bliss (EOB) values. EOB values above 0 indicate synergy, with higher values indicating higher levels of synergy. Expression of oncogenes was studied by Western blot and qPCR. 4E-BP1 was studied by Western blot and by 4E-BP1 cap-binding assay using m7GTP Sepharose beads. Translation was determined using a bicistronic reporter. Drug studies were validated by gene knockout of expected molecular targets such as CK1ε and PI3Kδ using CRISPR/Cas9. To further investigate the global effects of targeting translation initiation, we are conducting in parallel proteomic and RNA-Seq studies in 3 cell lines representing DLBCL, DHL, and MCL. Furthermore, the mechanism will be validated by rescuing experiments through over-expression of eIF4E, MYC, or CCND1. The efficacy of TGR-1202-containing regimens is being investigated in xenograft mouse models of MCL.Results: We investigated the combinatorial effect of TGR-1202 and the proteasome inhibitor carfilzomib. The combination of TGR-1202 and carfilzomib (TC) was highly synergistic in mantle cell lymphoma and double hit lymphoma cell lines (Figure 1A). TC synergistically inhibited phosphorylation of 4E-BP1 at the Ser65 in both MCL and DHL (Figure1B). The TC combination synergistically produced cleavage of poly-ADP ribose polymerase (PARP), indicating apoptosis as its mechanism (Figure 1C). TC reduced the protein expression levels of several oncogenes responsible for malignancies such as c-Myc, cyclin D1, and Bcl-2. In contrast, this combination had no significant effect on the mRNA level of c-Myc and cyclin D1 (Figure 1D).Conclusion: A novel therapeutic strategy can be developed by combining umbralisib/TGR-1202 and the proteasome inhibitor carfilzomib for the treatment of DLBCL, DHL, and MCL. The combination induces apoptosis by inhibiting the phosphorylation of 4E-BP1, leading to translational silencing and suppressed protein levels of c-Myc, cyclin D1, and Bcl-2. [Display omitted] DisclosuresAli:Onconova Therapeutics: Consultancy; Kura Oncology: Consultancy. O'Connor:Celgene: Honoraria, Research Funding; Trillium Therapeutics: Research Funding.

THE COMBINATION OF DUVELISIB AND ROMIDEPSIN (DR) IS HIGHLY ACTIVE AGAINST RELAPSED/REFRACTORY PERIPHERAL T‐CELL LYMPHOMA WITH LOW RATES OF TRANSAMINITIS: FINAL RESULTS

Introduction: Standard therapies for most relapsed/refractory (R/R) T-cell lymphomas (TCL) have overall response rates (ORR) of 25%-35%. Phosphoinositide-3-kinase (PI3K) δ and γ isoforms can promote tumor cell autonomous and nonautonomous effects in TCL. Initial studies of the PI3K-δ/γ inhibitor duvelisib (D) in R/R TCL showed an ORR of 50% and CR of 19%, but also a 40% rate of grade (Gr) 3/4 ALT elevation at the MTD of 75 mg BID (Horwitz et al Blood 2018). Based on preclinical data, we initiated a phase I study of D with either romidepsin (R) or bortezomib. Based on efficacy and safety, Arm A (DR) was expanded to further describe safety and subtype-specific efficacy. Methods: 66 patients were treated on Arm A, with 59 at the MTD of D 75mg BID + R 10 mg/m2 on days 1, 8, 15 of a 28 day cycle with prophylaxis against VZV and PJP. Response was assessed q2 cycles x 3 then q3 cycles. 10 patients received 1 cycle (Lead In) of D 75 mg BID alone prior to combination DR. Patients proceeding to transplant were censored. Results: 55 patients with PTCL and 11 with CTCL were treated (Table 1). No DLTs were seen in the phase 1 on Arm A so dose level 3 (D 75 + R 10) was deemed the MTD. At the MTD, 50/59 (85%) had AEs Gr 3-4 (no Gr 5) possibly related to study drug. AEs ≥Gr 3 in ≥10% of pt were: neutropenia (36%), diarrhea (15%), increased ALT/AST (14%), thrombocytopenia (10%), and infection (10%). 5 patients (9%) had ≥Gr 3 rash. 12 had any Gr oropharyngeal/esophageal candidiasis; 2 Gr3. In 10 patients who began on D-only Lead In, 4 (40%) had ≥Gr 3 ALT/AST and 3/10 had ≥Gr 3 diarrhea. By contrast, only 4 /49 (8%) who got R + D in cycle 1 had Gr 3-4 ALT/AST (p = .022) and 6/49 had ≥Gr 3 diarrhea (p = .170). 64/66 patients were evaluable for response. ORR was 55% (35/64) and CR was 34% (22/64). In PTCL, ORR was 58% (31/53) and CR was 42% (22/53). In CTCL, ORR was 36% (4/11), all PR. Response by histology is in Table 1. Of responders, 15/35 (43%) proceeded to allo-SCT with curative intent, after a median of 4 cycles. Median PFS was 6.9 m (PTCL) and 5.5 m (CTCL) and median DOR was 8.1 m. 4 subjects had CR to single agent D on Lead-in and did not proceed to DR; 2/4 went to SCT and 1/4 remains on D at 42m. Conclusion: DR is highly active in R/R PTCL. Adding Romidepsin to Duvelisib 75 mg BID is safe and reduces Gr 3-4 transaminitis compared to Duvelisib at the same dose. The high rates of CR and frequent bridging to allotransplant support the value of DR for patients with R/R PTCL. The research was funded by Verastem/SecuraBio for this clinical trial Keywords: Aggressive T-cell non-Hodgkin lymphoma, Chemotherapy, Combination Therapies Conflicts of interests pertinent to the abstract S. M. Horwitz Consultant or advisory role: Acrotech Biopharma, ADC Therapeutics, Astex, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Bio, Takeda, Trillium Therapeutics, Tubulis, Verastem, SecuraBio, and Vividion Therapeutics. Honoraria: Takeda Research funding: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium/Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio A. J. Moskowitz Consultant or advisory role: Imbrium Therapeutics L.P, Janpix Ltd., Merck, Seattle Genetics, and Takeda Research funding: ADC Therapeutics, Miragen, Seattle Genetics, Merck, Bristol-Myers Squibb, and Incyte N. Mehta-Shah Consultant or advisory role: Kiowa Hakka Kirin, Karyopharm Therapeutics, C4 Therapeutics, Daiichi Sankyo, Ono Pharmaceuticals, SecuraBio Research funding: Bristol Myers Squibb, Celgene, Verastem, Innate Pharmaceuticals, Corvus Pharmaceuticals, Genentech/Roche D. C. Fisher Consultant or advisory role: Verastem A. Kumar Consultant or advisory role: Celgene, Kite Pharmaceuticals Research funding: Abbvie Pharmaceuticals, Adaptive Biotechnologies, Pharmacyclics, Seattle Genetics, Astra Zeneca – Steering Committee for MCL Registry A. Dogan Consultant or advisory role: Corvus Pharmaceuticals, Physicians’ Education Resource, Seattle Genetics, Takeda, Roche, EUSAPharma, PeerView Research funding: Roche and Takeda D. Weinstock Consultant or advisory role: Secura Pharma Research funding: Verastem

Outcomes for Patients with &lt;i&gt;IDH&lt;/i&gt;-Mutated Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

Background: Disease relapse after hematopoietic cell transplantation (HCT) is a major cause of treatment failure for patients with acute myeloid leukemia (AML). Maintenance therapy following HCT for patients with targetable mutations such as mutated IDH1 or IDH2 may improve outcomes, and clinical trials evaluating this strategy are ongoing. However, current clinical outcomes of IDH1 - and IDH2 -mutated AML patients following HCT have not been well-described. Methods: In this multicenter retrospective analysis, 112 adult patients with either IDH1 - or IDH2 -mutated AML who underwent HCT were identified at Massachusetts General Hospital, Dana Farber Cancer Institute, and Ohio State University. Mutation testing was performed using next-generation sequencing panels. Patient characteristics were collected retrospectively, and their outcomes — including progression-free survival (PFS), overall survival (OS), relapse, and non-relapse mortality — were analyzed. Findings: The median patient age was 64·1 years. 78·5% of patients had intermediate- or adverse-risk disease by European LeukemiaNET criteria. Commonly detected co-mutations were DNMT3A (35·7%), NPM1 (33·1%), and FLT3-ITD (13·4%). The median follow-up was 27·5 months. For IDH1- mutated patients, the 1- and 2-year PFS was 75% and 58%, respectively, and the 1- and 2-year OS was 78% and 74%, respectively. For IDH2- mutated patients, the 1- and 2-year PFS was 64% and 58%, respectively, and the 1- and 2-year OS was 75% and 68%, respectively. Interpretation: Our analysis provides important benchmarks for analysis and interpretation of results emerging from ongoing clinical trials evaluating maintenance IDH1 and IDH2 inhibitor therapy for AML patients following HCT. Funding: This project has no funding source to report. Declaration of Interests: Dr. Eisfeld reports other from Karyopharm, personal fees from Vigeo, outside the submitted work. Dr. E Chen has nothing to disclose. Dr. Li has nothing to disclose. Dr. Luskin has nothing to disclose. Dr. Mims reports other from Jazz, other from Syndax, other from Abbvie, other from Kura oncology, personal fees from Agios, other from Novartis, outside the submitted work. Dr. Jones reports personal fees from Pharmacyclics LLC, outside the submitted work. Dr. Antin has nothing to disclose. Dr. Cutler reports other from Incyte, other from Kadmon, other from Jazz, other from Medsenic, other from Generon, other from Mesoblast, outside the submitted work. Dr. Koreth reports personal fees from Equilium, personal fees from Amgen, personal fees from Moderna Therapeutics, personal fees from Biolojic Design, personal fees from EMD Serono, other from Therakos, other from Cugene, grants from Miltenyi, grants from BMS, grants from Reneron, other from Clinigen, outside the submitted work. Dr. Gooptu has nothing to disclose. Dr. Romee has nothing to disclose. Dr. El-Jawahri has nothing to disclose. Dr. McAfee has nothing to disclose. Dr. Defilipp reports grants from Incyte, grants from Regimmune, personal fees from Syndax, outside the submitted work. Dr. Soiffer reports other from Kiadis, other from Gilead, other from Rheos, other from Cugene, other from Precision Bioscience, other from Mana Therapeutics, other from VOR Biopharma, other from Novartis, other from Juno, other from Celgene, other from Alexion, other from National Marrow Donor Program, outside the submitted work. Dr. YB Chen reports personal fees from Incyte, personal fees from Takeda, personal fees from Magenta, personal fees from Kiadis, other from Actinium, other from Equilium, other from Abbvie, outside the submitted work. Dr. Fathi reports grants from Takeda, personal fees from Boston Biomedical, personal fees from PTC Therapeutics, personal fees from Amphivena, personal fees from Astellas, personal fees from Daiichi Sankyo, personal fees from Novartis, grants and personal fees from Celgene/BMS, personal fees from Trovagene, personal fees from Forty Seven , personal fees from NewLink Genetics , personal fees from Pfizer, personal fees from Abbvie, grants and personal fees from Seattle Genetics , grants and personal fees from Agios, personal fees from Amgen, personal fees from Trillium, personal fees from Kura Oncology, personal fees from Blueprint, personal fees from Genentech, outside the submitted work. Ethics Approval Statement: This study was approved by the Institutional Review Boards at the Dana-Farber Harvard Cancer Center and Ohio State University Comprehensive Cancer Center

Transcriptomics in Tumor and Normal Tissues and Precision Oncology Algorithms Identify Early-Stage NSCLC Patients with High Risk of Post-Surgery Recurrence Who May Benefit from Adjuvant Therapies

Background: The prognosis of patients with non-small cell lung cancer (NSCLC) is traditionally determined by anatomic staging using the Tumor, Node, Metastasis (TNM) staging system. TNM staging neglects the biological features of the tumor that may be important in determining patient outcome and guiding therapeutic interventions. Identifying NSCLC patients at increased risk of recurrence after curative-intent surgery remains an important unmet need as adjuvant therapies are available that may reduce the risk of recurrence and improve patient survival. Methods: Digital Display Precision Predictor (DDPP), based on differential RNA expression in tumor versus normal tissue, was used to interrogate gene sets to determine their association with disease-free survival (DFS) in patients with non-small cell lung cancer (NSCLC) who underwent curative-intent surgery. Findings: Low versus high DDPP score was significantly associated with shorter DFS (highest recurrence risk): HR=1.88, 95% CI [1.2-2.9] (p=0.006) in all patients (n=120) and in patients with TNM stages 1-2 (p= 0.00051) (n=83). For patients with stages 1-2 and low DDPP (n=29), adjuvant chemotherapy was associated with improved DFS (p= 0.0041). High co-overexpression of CTLA-4, PD-L1 and ICOS in normal lung (28 of 120 patients), hypothesized to reflect the host immune status, was also significantly associated with decreased DFS (p= 0.0013) suggesting an immune tolerance to tumor neoantigens in some patients. Patients with DDPP low and immunotolerant normal tissue had the shortest DFS (p=2.12E-11). Interpretation: We identified stage 1-2 NSCLC patients with high risk of recurrence who benefitted from adjuvant chemotherapy. Furthermore, identified a subset of NSCLC patients who may have poor post-surgery outcome related to an immunotolerant normal tissue profile that might be amenable to modulation by specific checkpoint blockade immunotherapies. Funding: European Union Frame Pprogram 6-funded project (Chemores FP6 Health, Grant 37 665). Declaration of Interest: Dr. Vladimir Lazar, Catherine Bresson, are full time employees of Worldwide Innovative Network (WIN) Association - WIN Consortium. Worldwide Innovative Network (WIN) Association - WIN Consortium is the owner of the patent family entitled Digital Display. The inventors are Dr. Vladimir Lazar, and Shai Magidi. Dr. Jean-Francois Martini, is a full-time employee and stockholder of Pfizer Inc. Dr. Susan Galbraith is a full-time employee and stockholder of AstraZeneca. Dr. Benjamin Solomon received honorarium for Advisory Board from AstraZeneca and Bayer. Shai Magidi receives consultancy from Worldwide Innovative Network (WIN) Association. Dr. Amir Onn receives consulting fees from Roche Israel, MSD Israel, Boehringer Ingelheim 552 and AstraZeneca. Dr. Enriqueta Felip receives advisory board and/or speaker’s bureau fee from Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffman-LaRoche, Glaxi Smith Kline, Janssen, Medical Trends, Medscape, Merck Sharp & Dohme, Merck Serono, Peptomyc, Peervoice, Pfizer, Puma, Regeneron, Sanofi, Springer, Syneos Health, Takeda, Touch Medical; on the board of Grifols, Independent member. Receives research funding from Fundacion Merck Salud, Grant for Oncology Innovation (GOI) EMD Serono. Dr. Josep Tabernero declares scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics. Dr. Gerald Batist collaborates in formal clinical trial contracts, IITs and in joint grants funded by Canadian and Quebec governments with Roche, Merck, Novartis, Astra-Zeneca, Bayer, Esperas, Aurka, Caprion, MRM. Pr. Angel Porgador declares scientific consultancy role for PiNK Biopharma. Dr. Razelle Kurzrock has received research funding from Genentech, Merck Serono, Pfizer, Boehringer Ingelheim, TopAlliance, Takeda, Incyte, Debiopharm, Medimmune, Sequenom, Foundation Medicine, Konica Minolta, Grifols, Omniseq, and Guardant, as well as consultant and/or speaker fees and/or advisory board for X-Biotech, Neomed, Pfizer, Actuate Therapeutics, Roche, Turning Point Therapeutics, TD2/Volastra, Bicara Therapeutics, Inc., and Biological Dynamics, has an equity interest in IDbyDNA and CureMatch Inc, serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch. Dr. Richard L. Schilsky’s institution (ASCO) receives research grants in support of a clinical trial that he directs from the following companies: AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Genentech, Lilly, Merck, Pfizer. Dr. Schilsky reports being a consultant to Cellworks, Clarify Precision Medicine, Bryologx, EQRx and Scandion Oncology. The remaining authors declare no competing interests. Ethical Approval: The bio-banking study was approved by the IMM’s Ethics Committee.

Preliminary Data on a Phase 1/2A First in Human Study of the Menin-KMT2A (MLL) Inhibitor KO-539 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Preliminary Data on a Phase 1/2A First in Human Study of the Menin-KMT2A (MLL) Inhibitor KO-539 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Complete Responses in Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients on a Weekly Dosing Schedule of Vibecotamab (XmAb14045), a CD123 x CD3 T Cell-Engaging Bispecific Antibody; Initial Results of a Phase 1 Study

Complete Responses in Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients on a Weekly Dosing Schedule of Vibecotamab (XmAb14045), a CD123 x CD3 T Cell-Engaging Bispecific Antibody; Initial Results of a Phase 1 Study

A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results

A Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML: Final Results

Enasidenib (ENA) Monotherapy with Addition of Azacitidine in Non-Responders Is Effective in Older Patients with Newly Diagnosed IDH2 Mutated Acute Myeloid Leukemia (AML): A Completed Phase 2/1b Sub-Study of the Beat AML Master Trial

Enasidenib (ENA) Monotherapy with Addition of Azacitidine in Non-Responders Is Effective in Older Patients with Newly Diagnosed IDH2 Mutated Acute Myeloid Leukemia (AML): A Completed Phase 2/1b Sub-Study of the Beat AML Master Trial

A Phase I Study of the IDH2 Inhibitor Enasidenib As Maintenance Therapy for IDH2-Mutant Myeloid Neoplasms Following Hematopoietic Cell Transplantation

A Phase I Study of the IDH2 Inhibitor Enasidenib As Maintenance Therapy for IDH2-Mutant Myeloid Neoplasms Following Hematopoietic Cell Transplantation

Outcomes of IDH1- and IDH2-Mutated AML Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

Outcomes of IDH1- and IDH2-Mutated AML Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies

Gilteritinib Remains Clinically Active in Relapsed/Refractory FLT3 Mutated AML Previously Treated with FLT3 inhibitors

Gilteritinib Remains Clinically Active in Relapsed/Refractory FLT3 Mutated AML Previously Treated with FLT3 inhibitors

Successful Treatment of Mature T-Cell Lymphoma with Allogeneic Stem Cell Transplantation: The Largest Multicenter Retrospective Analysis

Successful Treatment of Mature T-Cell Lymphoma with Allogeneic Stem Cell Transplantation: The Largest Multicenter Retrospective Analysis