Karyopharm Therapeutics Inc Research Articles

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. Karyopharm Therapeutics Inc.

Selinexor in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (SADAL): A Single-Arm Multinational Phase 2 Trial

Background: Relapsed or refractory diffuse large B‑cell lymphoma (RR DLBCL) is an aggressive cancer with a median survival of less than 6 months. The SADAL trial aims to assess the response to the oral selective inhibitor of nuclear export (SINE) selinexor in patients with RR DLBCL who have no therapeutic options of demonstrated clinical benefit. Methods: SADAL was a multicenter, open-label Phase 2b study conducted at 59 sites globally. Patients 18 years with previously treated, pathologically confirmed de novo DLBCL, or DLBCL transformed from previously diagnosed indolent lymphoma, and having received at least two prior therapies were enrolled. Germinal center B-cell (GCB) or non-GCB tumor subtype and double/triple expressor status were determined by immunohistochemistry and double/triple hit status was determined by cytogenetic assays. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The primary outcome was overall response rate (ORR) by central radiologic review. A modified intent-to-treat population was used for all efficacy endpoints. Findings: 127 patients were enrolled from October 21, 2015 through November 2, 2019. The ORR was 28.3% (95% CI: 20.7%, 37.0%), including complete response in 15 (11.8%) and partial response in 21 (16.5%) patients. Median overall survival (OS) was 9.1 months (95% CI: 6.6, 15.1) with longer OS observed in responding patients. Responses were observed across different subgroups regardless of age, gender, prior therapy, DLBCL subtype, refractory status or prior ASCT therapy. Adverse events were generally reversible and managed with dose modifications and/or standard supportive care. Interpretation: In both GCB- and non-GCB DLBCL subtypes, single agent oral selinexor induced durable responses which were associated with longer survival. Selinexor may be a new oral, non-cytotoxic treatment option for patients with RR DLBCL after two lines of chemo-immunotherapy. Trial Registration: This trial is registered at ClinicalTrials.gov, NCT02227251. Funding Statement: This study (NCT02227251) was funded by Karyopharm Therapeutics Inc, Newton, Massachusetts, USA, which provided all study materials. Declaration of Interests: NK reports research support from Verastem, Gilead, Celgene, and Roche, as well as honoraria from Gilead, Janssen, and Karyopharm. FC reports personal fees from Takeda, Gilead, and Janssen, outside the submitted work. MC reports personal fees from Celgene, Gilead, Janssen, Karyopharm, Novartis, Roche, Sandoz, and Servier outside the submitted work. GF reports personal fees from Karyopharm and Roche, outside the submitted work. AG reports personal fees and honoraria from AstraZeneca, personal fees and board membership from Cota and Kite/Gilead, personal fees from Janssen, Celgene, Acerta, and research funding from Constellation, Bayer, CALBG, Genentech, Hoffman-La Roche, MD Anderson, Morphosys, Pharmacyclics, and the University of Nebraska, outside the submitted work. OC reports grants, personal fees, and non-financial support from Roche, personal fees and non-financial support from Takeda, BMS, Amgen, Janssen, Abbvie, grants and personal fees from Gilead, and personal fees from Merck, outside the submitted work. BH reports grants and personal fees from Karyopharm, outside the submitted work. UJ reports personal fees from Karyopharm, during the conduct of the study; grants and personal fees from AbbVie, Celgene, Gilead, Janssen, Novartis, Roche, Takeda, Amgen, Miltenyi, and BMS, outside the submitted work. JMS reports honoraria from Roche, Janssen, Gilead, Celgene, Novartis outside the submitted work. MS reports personal fees from Karyopharm during the conduct of the study, and personal fees from Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Genentech, and Seattle Genetics, outside the submitted work. TPV reports honoraria from WinMedica, Astellas, and Gilead, honoraria, advisory board membership and research support from Takeda, honoraria and advisory board membership from Roche, Bristol, Genesis, and Novartis, advisory board membership at Janssen, honoraria and research support from Merck and Amgen, and research support from Pfizer and Karyopharm. AJ reports personal fees from Karyopharm Therapeutics during the conduct of the study. YL reports personal fees from Karyopharm Therapeutics, outside the submitted work. HC, YL, XM, KC, DM, HW, JS, JRS, SS, and MK are employees of Karyopharm. AJ is a consultant for Karyopharm. MK and SS are stockholders of Karyopharm. SS holds patents (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents (PCT/US12/048319, 499/2012, PI20102724, and 2012000928) on hydrazide-containing nuclear transport modulators and uses. All other authors declare no competing interests. Ethics Approval Statement: The institutional review board or independent ethics committee at each study center approved the protocol, and the study was performed in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.

Eltanexor (KPT-8602), a Second-Generation Selective Inhibitor of Nuclear Export (SINE) Compound, in Patients with Higher-Risk Myelodysplastic Syndrome

Background: Overexpression of exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (e.g. p53, IκB), and promotes the translation of eIF4E-bound mRNAs coding oncoproteins (e.g. c-MYC, BCL-2, AR). Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study, wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. Eltanexor (elta), a second-generation SINE compound, has demonstrated reduced brain penetration and improved tolerability compared to selinexor in non-clinical animal models, and preliminary anti-tumor activity in clinical trials of hematologic and solid tumor malignancies. The primary objective of this study was to assess the safety, tolerability and anti-tumor activity of elta in patients (pts) with higher risk (HR)-Myelodysplastic Syndrome (MDS). Methods: This is part of a Phase 1/2 study (NCT02649790) to determine the safety, tolerability and anti-tumor activity of elta in advance malignancies. This trial planned to evaluate single agent activity of elta in an expansion cohort of 20 pts with HR-MDS (intermediate-2 [Int-2] or high-risk by the International Prognostic Scoring System [IPSS]). Other key eligibility criteria included: age ≥18, ECOG ≥1, adequate organ function, and documented evidence of progressive disease as defined by the 2006 International Working Group (IWG) Response Criteria for MDS, which includes hypomethylating agent (HMA) failure. The dose levels evaluated in the MDS cohort were 10 and 20 mg elta taken orally once daily for 5 consecutive days per week in a 28-day cycle. A key efficacy endpoint is overall response rate (ORR) which includes complete response (CR), partial response (PR), marrow CR (mCR), and hematologic improvement (HI) using the 2006 IWG Response Criteria for MDS. Results: Twenty pts (median age 77 years-old; range 62-89; 55% male) were enrolled as of 15 July 2018 (n=15 at 20 mg and n=5 at 10 mg). All pts were refractory to HMA with a median of 2 prior therapies (range 1 - 5) and 90% high risk via IPSS (11 pts high, 7 pts Int-2, 2 pts Int-1 [IPSS-R high]). Fourteen of 20 pts were evaluable for response, 2 are pending disease reassessment and 4 were not evaluable (NE). Preliminary efficacy demonstrated best responses of 4 mCR (29%) and 6 stable disease (SD; 43%) and 4 progressive disease (PD; 29%). The disease control rate (mCR + SD) was 71%. The median time on treatment for all pts was 69 days (range 5+ - 379) with a median time on study of 115 days (range 5+ - 400). The most frequent (≥3 pts) treatment-related adverse events (TRAEs) any grade (Gr) included nausea (53%), decreased appetite (33%), diarrhea (27%), thrombocytopenia, anemia, neutropenia, vomiting and dysgeusia (20% each). The most frequent Gr≥3 TRAEs included thrombocytopenia and anemia which are expected in this immune compromised patient population. All AEs were reversible and manageable by supportive care and dose modification. The 4 pts NE for response were pts who discontinued from treatment before having the first disease response reassessment due to: Gr3 diarrhea related to eltanexor, Gr5 sepsis not related per investigator, Gr3 pneumonia not related, and withdrawal by pt. Conclusion: Oral eltanexor demonstrated preliminary anti-tumor activity as a single agent in elderly pts with HMA-refractory HR-MDS, including mCRs or disease stabilization, and a manageable tolerability profile. Further evaluation of efficacy and safety in HR-MDS is on-going. Disclosures Lee: Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Bhatnagar:Karyopharm Therapeutics: Other: Research support; Novartis and Astellas: Consultancy, Honoraria; Cell Therapeutics, Inc.: Other: Research support. Senapedis:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties. Baloglu:Karyopharm Therapeutics Inc: Equity Ownership, Patents & Royalties; resTORbio: Employment. Wang:Karyopharm Therapeutics Inc: Employment. Shah:Karyopharm Therapeutics Inc: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Overall Survival of Triple Class Refractory, Penta-Exposed Multiple Myeloma (MM) Patients Treated with Selinexor Plus Dexamethasone or Conventional Care: A Combined Analysis of the STORM and Mammoth Studies

Overall Survival of Triple Class Refractory, Penta-Exposed Multiple Myeloma (MM) Patients Treated with Selinexor Plus Dexamethasone or Conventional Care: A Combined Analysis of the STORM and Mammoth Studies

Response to Therapy and the Effectiveness of Treatment with Selinexor and Dexamethasone in Patients with Penta-Exposed Triple-Class Refractory Myeloma Who Had Plasmacytomas

Response to Therapy and the Effectiveness of Treatment with Selinexor and Dexamethasone in Patients with Penta-Exposed Triple-Class Refractory Myeloma Who Had Plasmacytomas

Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma

Safety and Efficacy of the Combination of Selinexor, Lenalidomide and Dexamethasone (SRd) in Patients with Newly Diagnosed Multiple Myeloma

Influence of Cytogenetics in Patients with Relapsed Refractory Multiple Myeloma Treated with Oral Selinexor and Dexamethasone: A Post-Hoc Analysis of the STORM Study

Influence of Cytogenetics in Patients with Relapsed Refractory Multiple Myeloma Treated with Oral Selinexor and Dexamethasone: A Post-Hoc Analysis of the STORM Study

A Phase 1b/2 Study of Selinexor, Carfilzomib, and Dexamethasone (SKd) in Relapsed/ Refractory Multiple Myeloma (RRMM)

A Phase 1b/2 Study of Selinexor, Carfilzomib, and Dexamethasone (SKd) in Relapsed/ Refractory Multiple Myeloma (RRMM)

A Machine Learning Approach Identifies a 30-Gene Model That Predicts Sensitivity to Selinexor in Multiple Myeloma

A Machine Learning Approach Identifies a 30-Gene Model That Predicts Sensitivity to Selinexor in Multiple Myeloma

Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma

Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma

Dual Inhibition of MDM2 and XPO1 Synergizes to Induce Apoptosis in Acute Myeloid Leukemia Progenitor Cells with Wild-Type TP53 through Nuclear Accumulation of p53 and Suppression of c-Myc

Dual Inhibition of MDM2 and XPO1 Synergizes to Induce Apoptosis in Acute Myeloid Leukemia Progenitor Cells with Wild-Type TP53 through Nuclear Accumulation of p53 and Suppression of c-Myc

E2F1 Is a Biomarker of Selinexor Resistance in Relapsed/Refractory Multiple Myeloma Patients

Selinexor (KPT-330) is a selective inhibitor of nuclear export (SINE) which specifically targets XPO1 (Exportin 1)-mediated nuclear export, leading to increased nuclear retention of major tumor suppressor proteins and inducing selective apoptosis in cancer cells. Several phase I and II clinical trials demonstrate evidence of anti-cancer activity of Selinexor in solid tumors (i.e metastatic prostate cancer (PMID: 29487219), advanced refractory bone or soft tissue sarcoma (PMID: 27458288) and non-small cell lung cancer (PMID: 28647672); as well as, hematological malignancies, including non-Hodgkin lymphoma (PMID: 28468797), acute myeloid leukemia (PMID: 29304833) and multiple myeloma (MM) (PMID: 29381435). In the STORM (Selinexor Treatment of Refractory Myeloma) trial, the combination of Selinexor with dexamethasone in MM patients refractory to bortezomib, carfilzomib, lenalidomide and pomalidomide (quad-refractory), or in addition, to daratumumab (penta-refractory), has shown an overall response rate (ORR) of 21% (Vogl et al, JCO 2018). Our objective is to identify biomarkers for selection of patients at higher likelihood of clinical benefit from Selinexor salvage and understand mechanisms of Selinexor resistance.We therefore analyzed transcriptional differences using RNA sequencing in CD138+ cells from bone marrow aspirates obtained prior to treatment from 32 MM patients enrolled in STORM. The raw data (fastq) was mapped by using the tool STAR and gene-level annotated by featureCounts. Patients were split in two groups based on their progression-free survival (PFS). Differential expression analysis was performed using the tool DESeq2, which enables a more quantitative analysis of comparative RNA-seq data using shrinkage estimators for dispersion and fold change. The results revealed significant up-regulation of 13 genes in patients with PFS < 120 days (n = 21, p < 0.05) versus patients with PFS > 120 days (n=11), including the transcription factor E2F1 and its targets MYBL2, FANCA, GINS3 and SLX4 (Fig. 1).Next, we evaluated the expression of E2F1 in another set of 26 patients from the STORM trial by Affymetrix U133 gene expression microarrays. Data was analyzed using the Signal Space Transformation (SST)-Robust Multi-Chip Analysis (RMA) algorithm. Patients with PFS < 120 days (n = 19) exhibited significant up-regulation of E2F1 (p < 0.05) (Fig. 2).E2F1 is a transcription factor that regulates cell cycle G1/S progression. At rest, E2F1 is complexed with its negative regulator retinoblastoma(RB) protein. Upon phosphorylation of RB by the Cyclin D1-CDK4/6 complex, pRB is inactivated allowing E2F1 to commence transcription of target genes allowing G1/S progression. E2F transcription factors are exported by XPO1 from the nucleus to the cytoplasm. We treated RPMI8226 (IC50=150nM) and MM1S (IC50=25nM) human myeloma cell lines with Selinexor at IC50 and examined nuclear vs cytoplasmic expression of E2F1 after 24 and 48 hours by western blotting. Our results demonstrated nuclear retention of E2F1 following treatment of HMCLs with Selinexor and suggest a model where overexpression of E2F1 overwhelms the nuclear export mechanism and may result in downstream gene programming that confers a proliferative advantage in cells, manifested by rapid progression (<120 days) in patients.Our findings suggest a model where E2F1 expression may be a biomarker of Selinexor resistance. We are currently validating our findings in additional samples from patients with MM treated with Selinexor. [Display omitted] DisclosuresCrochiere:Karyopharm Therapeutics Inc: Employment. Landesman:Karyopharm Therapeutics Inc: Employment. Chari:Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; The Binding Site: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cho:Janssen: Consultancy; Genentech Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; J & J: Consultancy; Agenus Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Barlogie:Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; Millenium: Consultancy, Research Funding; Dana Farber Cancer Institute: Other: travel stipend; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend; Celgene: Consultancy, Research Funding; Multiple Myeloma Research Foundation: Other: travel stipend; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; Merck: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Medicom: Speakers Bureau.

FT-2102, an IDH1m Inhibitor, in Combination with Azacitidine in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Ayndrome (MDS): Results from a Phase 1 Study

Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients. Mutated IDH1 metabolizes alpha-ketoglutarate into 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Azacitidine (AZA), a hypomethylating agent (HMA), is a standard of care for MDS and for AML patients unfit for intensive therapy. We present Phase 1 clinical data from the ongoing Phase 1/2 study of FT-2102 in combination with azacitidine (FT-2102+AZA) in patients with IDH1m AML and MDS (CT.gov: NCT02719574). Methods: A Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion. FT-2102 was administered daily (150 QD or 150 BID) until disease progression or unacceptable toxicity; AZA was administered at 75 mg/m2 IV or SC daily for 7 days of each 28-day cycle. Eligible patients had IDH1m AML/MDS that was relapsed/refractory (R/R) or treatment-naive (TN), were eligible for AZA therapy and had adequate liver and renal function. Prior IDH1 inhibitors and hypomethylating agents were allowed, and there were no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03. Results: At the time of the data cutoff, 07 April 2018, 27 patients had been enrolled and 26 had been treated with FT-2102+AZA, with a median of 3 months on treatment (range: 0.2 to 12 months). Of the 27 enrolled patients, 24 had AML (20 R/R; 4 TN) and 3 patients had MDS (all TN). The median number of prior antileukemia therapies was 3 (range: 0-5) in the AML patients. Doses of FT-2102 were 150 mg QD (n=7) and 150 mg BID (n=20). Thirteen (50%) patients discontinued treatment, with the most common reasons for treatment discontinuation were hematopoietic stem cell transplant (n=4), death (n=2), and progressive disease (n=2). No patients discontinued due to an AE. Severe (≥ Grade 3) AEs occurring in ≥ 5% of patients included febrile neutropenia (27%), anemia, thrombocytopenia, leukocytosis (19% each), fatigue, hypertension, neutropenia (15% each), nausea, pneumonia, hypokalemia (12% each) and abdominal pain (8%). Three patients had differentiation syndrome (IDH-DS), which resolved with FT-2102 temporary interruption, and treatment with dexamethasone, hydroxyurea, and supportive care in all three. Five patients died within 28-days of the last dose of study drug, none of which were considered related to FT-2102+AZA. No DLTs were observed during dose escalation. PK analysis demonstrated no impact of AZA on steady-state exposure of FT-2102. 2-HG levels to normal levels by C2D1. Table 1 shows the Investigator-assessed ORR per IWG. Responses have been seen as early as 1 month on treatment, and stable disease for greater than 6 months; 50% of patients remain on treatment. Conclusions: FT-2102+AZA is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Clinical activity has been observed, with an ORR of 42%. Durable CRs (>12 months) have been observed. The current data support the continued evaluation of FT-2102 150 mg BID+AZA in the Phase 2 study. Three Phase 2 combination therapy cohorts are currently open for enrollment in patients Disclosures Cortes:Pfizer: Consultancy, Research Funding; Arog: Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Wang:Amgen: Consultancy; Jazz: Speakers Bureau; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Ferrell:Incyte: Research Funding. Jonas:LP Therapeutics: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding; Daiichi Sankyo: Research Funding; Kalobios: Research Funding; Glycomimetics: Research Funding; AbbVie: Consultancy, Research Funding; Forma: Research Funding; Accelerated Medical Diagnostics: Research Funding; Tolero: Consultancy; Esanex: Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding. Wei:Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Pfizer: Honoraria, Other: Advisory committee; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Amgen: Honoraria, Other: Advisory committee, Research Funding; Celgene: Honoraria, Other: Advisory committee, Research Funding. Montesinos:Novartis: Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Speakers Bureau. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment.

Phase 1 Study of the IDH1m Inhibitor FT-2102 As a Single Agent in Patients with IDH1m Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients and produce 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Herein, we present preclinical and clinical data from an ongoing Phase 1/2 study of single-agent (SA) FT-2102 in patients with IDH1m AML and MDS (CT.gov: NCT02719574).Methods: Extensive pre-clinical evaluations were performed on FT-2102, including CYP interactions in-vivo in rat and in-vitro in human tissue and in-vivo QTc toxicology in monkeys. The clinical Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion phases. FT-2102 was administered daily until disease progression or unacceptable toxicity. Eligibility criteria included: IDH1m AML/MDS [relapsed/refractory (R/R) or treatment naïve (TN) for whom standard therapy was contraindicated], adequate liver and renal function, no prior IDH1 inhibitors, and no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03.Results: Evaluation of FT-2102 in in-vivo rat and in-vitro human tissue indicated hepatic metabolism by CYP enzymes (CPY3A4, 2C9, 1A1) as the major route of excretion. Animal toxicology studies predicted the threshold for QTc risk occurred at exposures >5.5 fold higher than the murine exposure at which 90% 2-HG reduction was observed.In the clinical study, at the time of the data cutoff, 31 patients (pts) had been treated with SA FT-2102, with a median of 3 mo. on treatment (range: 0.2 to 20 mo.). Of the 31pts treated, 25 had AML (22 R/R; 3 TN) and 6 had MDS (4 R/R; 2 TN). The median number of prior anti-leukemia therapies was 2 (range: 0-9) for AML pts and 1 (range: 0-4) for MDS pts. FT-2102 doses were: 150 mg QD (n=8), 300 mg QD (n=4), 150 mg BID (n=16), and 100 mg QD with food (n=3). Eighteen pts discontinued treatment, most commonly due to death (n=5), progressive disease (n=5), HSCT (n=3), or lack of response (n=3).Severe (≥Grade 3) AEs occurring in >5% of pts included thrombocytopenia (26%), febrile neutropenia (23%), anemia (19%), pneumonia (13%), neutropenia (7%), hypokalemia (7%), pyrexia (7%) and leukocytosis (6%). Three pts had differentiation syndrome (IDH-DS), which resolved with temporary interruption of FT-2102, treatment with dexamethasone, hydroxyurea, and supportive care in all three. One pt had transient QTcF prolongation (Grade 3) which resolved with temporary interruption of FT-2102 and cessation of suspected concomitant medications. Eight pts died on treatment or within 28 days of the last dose, with no deaths considered related to FT-2102. No DLTs were observed during dose escalation.Selection of FT-2102 150 mg BID as the RP2D was supported by PK and PD data. Durable steady-state (Css) achieved by Week 2 was well below the threshold for QTc risk predicted by preclinical studies. The predicted IC90 was confirmed with prompt and durable 2-HG reduction to normal levels by C2D1 at the RP2D.Table 1 shows the Investigator-assessed ORR per IWG. Responses have been observed from 1 to 6 months on treatment, with stable disease observed beyond 6 months; 42% of the patients remain on treatment.Conclusions: FT-2102 preclinical evaluations suggest a low risk of clinically significant CYP-mediated drug-drug interaction and QTc prolongation. SA FT-2102 is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Significant clinical activity has been observed in heavily pre-treated and in TN patients, both in AML and MDS. FT-2102 continues being investigated at a dose of 150 mg BID in a Phase 2 study. Three SA Phase 2 cohorts are currently open for enrollment in R/R AML, AML/MDS with CR/CRi (i.e., with MRD), and in pts with R/R MDS/AML with prior exposure to an IDH1m inhibitor. Data updates will be available at the time of presentation. [Display omitted] DisclosuresLee:LAM Therapeutics: Research Funding; Karyopharm Therapeutics Inc: Consultancy; AstraZeneca: Consultancy; Clinipace: Consultancy; Amgen: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Ferrell:Incyte: Research Funding. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment. Cortes:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Intermediate or High Risk Relapsed/Refractory Myelofibrosis

Background: Patients with myelofibrosis (MF) that have failed or are intolerant to JAK inhibitors (JAKi) have no standard treatment options. Tagraxofusp (Elzonris™; SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on a variety of malignancies, including certain myeloproliferative neoplasms (MPNs) such as MF. CD123 is also expressed on plasmacytoid dendritic cells (pDCs), which reside in the tumor microenvironment and may play a role in promoting growth of MPNs and other malignancies. Therefore, targeting of CD123-expressing malignant cells and/or neighboring pDCs may offer a novel therapeutic approach. Tagraxofusp has demonstrated high levels of clinical activity against blastic plasmacytoid dendritic cell neoplasm (BPDCN), a CD123+ malignancy derived from pDCs.Methods: This multicenter, two-stage Phase 1/2 trial is enrolling patients with MF that were relapsed, refractory, or unable to tolerate JAKi. Primary objectives include assessment of safety, determining optimal dose/regimen, and evaluating efficacy outcomes. In the Stage 1 dose escalation cohort (completed), tagraxofusp was dosed as a daily IV infusion at 7, 9, and 12 mcg/kg/day, on days 1-3 every 21 days (cycle 1-4), every 28 days (cycles 5-7), and every 42 days (cycles 8+). In Stage 2 (ongoing), patients received the optimal dose determined in Stage 1 (12 mcg/kg/day).Results: As of July 2018, 18 patients with MF received tagraxofusp. Five patients were treated in the second line setting and 12 patients were treated in third-line setting, and beyond. Median age was 69 years (range 55-81); 60% patients were female. Of the 18 patients with DIPSS Plus risk group assessment available, 3 patients (17%) were intermediate-1, 10 patients (55%) were intermediate-2, and 5 patients (28%) were high-risk. Median platelet count was 66 K/uL (range 15-579). 70% (14/20) of patients had baseline platelets <100K/uL, of which 6 patients had platelets <50K/uL at study entry. 89% (17/19) of patients had baseline splenomegaly defined as palpable spleen 5 cm or more below costal margin (BCM) by physical exam. Most common treatment-related adverse events (TRAEs) include hypoalbuminemia and thrombocytopenia (each 27%), and alanine aminotransferase increased, anemia, dizziness, fatigue, headache and nausea (each 20%). Most common ≥grade 3 TRAEs include anemia (20%) and thrombocytopenia and fatigue (each 7%). Capillary leak syndrome was reported in 1 patient (5%; grade 3). 50% (6/12) of evaluable patients, with baseline spleen size 5 cm or more BCM, had a spleen response, of which 33% (4/12) had splenomegaly reduction by 33% or more and 25% (3/12) had splenomegaly reduction by 35% or more. 50% (3/6) of patients with spleen response had treatment duration 8+ months, including 8+, 12+ and 14+ months (all 3 ongoing). Four patients with baseline thrombocytopenia had treatment durations 8+ months, 3 of which are ongoing.Conclusions: Tagraxofusp monotherapy demonstrated improvements in splenomegaly, with a manageable safety profile, in patients with relapsed/refractory MF, an area of unmet medical need. Given CD123 expression on myeloid neoplastic cells and pDCs in the tumor microenvironment, tagraxofusp may offer a novel targeted approach for MF patients. Enrollment continues, and updated safety and efficacy data will be presented. Registrational designs are being evaluated. Clinical trial information: NCT02268253. DisclosuresPemmaraju:celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; samus: Research Funding; novartis: Research Funding; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding. Gupta:Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schiller:Pharmacyclics: Research Funding; Celator/Jazz Pharmaceuticals: Research Funding. Lee:LAM Therapeutics: Research Funding; AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; Amgen: Consultancy. Yacoub:Ardelyx, INC.: Equity Ownership; Cara Therapeutics: Equity Ownership; Dynavax: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Ali:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Olguin:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Khoury:Stemline Therapeutics: Research Funding.

Results from Ongoing Phase 1/2 Clinical Trial of Tagraxofusp (SL-401) in Patients with Relapsed/Refractory Chronic Myelomonocytic Leukemia (CMML)

Background: Patients with chronic myelomonocytic leukemia (CMML) have historically had poor outcomes, with overall response rates (ORR) of ~16% for hypomethylating agents (HMA) in first-line registration studies with a median overall survival (OS) of ~4-7 months in the relapsed/refractory (R/R) setting. Allogeneic stem cell transplant is not an option for the majority, due to older age at diagnosis and comorbidities. Tagraxofusp (Elzonris™, SL-401) is a novel targeted therapy directed to the interleukin-3 receptor-α (CD123), a target expressed on a variety of malignancies. In CMML, CD123 is expressed on malignant progenitor cells as well as microenvironmental plasmacytoid dendritic cell (pDC) infiltrates, now shown to be part of the malignant clone (Solary, EHA 2018). We thus hypothesized that therapeutic targeting of CD123-expressing malignant cells and infiltrating clonal pDCs may offer a novel therapeutic approach. Tagraxofusp has already demonstrated high levels of clinical activity against blastic plasmacytoid dendritic cell neoplasm (BPDCN), a CD123+ malignancy derived from pDCs.Methods: This multicenter, two-stage Phase 1/2 trial is enrolling patients with relapsed/refractory (r/r) CMML or other myeloproliferative neoplasms (MPNs). Primary objectives include assessment of safety, determining optimal dose/regimen, and evaluating efficacy outcomes in patients with r/r CMML. In the Stage 1 dose escalation cohort (completed), tagraxofusp was administered as a daily IV infusion at 7, 9, and 12 mcg/kg/day, on days 1-3 every 21 days (cycle 1-4), every 28 days (cycles 5-7), and every 42 days (cycles 8+). In Stage 2 (ongoing), patients received the optimal dose determined in Stage 1 (12 mcg/kg; no MTD reached).Results: As of July 2018, 18 patients with CMML (CMML-1 [n=10]; CMML-2 [n=8]) received tagraxofusp. 13 patients were treated in second-line setting and 5 patients were treated in third-line and beyond, with HMAs being the most commonly administered prior therapy. Median age was 70 years (range 42-80); 78% patients were male. 53% (9/17) of patients had baseline splenomegaly (range: 2 to 22 cm palpable below left costal margin (BCM) by physical exam). Most common treatment-related adverse events (TRAEs) were hypoalbuminemia and nausea (each 38%), vomiting (31%), fatigue, edema, and thrombocytopenia (each 25%). Most common ≥grade 3 TRAEs were thrombocytopenia (13%) and nausea (6%). Capillary leak syndrome was reported in 3 patients (19%; all grade 2). 100% (8/8) of patients with baseline splenomegaly had a spleen response, including 75% (6/8) who had reduction in splenomegaly of 50% or more. 60% (3/5) of patients with baseline spleen size ≥5cm had reduction in splenomegaly of 50% or more. Two patients treated with tagraxofusp achieved bone marrow CRs. 43% (6/14) of evaluable patients had a treatment duration of 6 months or more, including one at 8+ and one at 14+ months.Conclusions: Tagraxofusp monotherapy resulted in significant reductions in spleen sizes along with bone marrow morphological responses in relapsed/refractory patients with CMML, with a manageable safety profile. Given CD123 expression on both neoplastic myeloid cells and pDCs infiltrates, tagraxofusp may offer a novel targeted approach for patients with CMML, an area of unmet medical need. Enrollment continues, and updated safety and efficacy data will be presented. A registrational trial in this patient population is planned. Clinical trial information: NCT02268253. DisclosuresAli:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Yacoub:Cara Therapeutics: Equity Ownership; Ardelyx, INC.: Equity Ownership; Dynavax: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sardone:Stemline Therapeutics: Employment, Equity Ownership. Wysowskyj:Stemline Therapeutics: Employment, Equity Ownership. Shemesh:Stemline Therapeutics: Employment, Equity Ownership. Chen:Stemline Therapeutics: Employment, Equity Ownership. Olguin:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership. Dunn:Stemline Therapeutics: Employment, Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Khoury:Stemline Therapeutics: Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; novartis: Research Funding; Affymetrix: Research Funding; samus: Research Funding; cellectis: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding; plexxikon: Research Funding; abbvie: Research Funding; SagerStrong Foundation: Research Funding.

Correlations between Pre-Transplant Treatment and Bone Marrow Response with Post-Transplant Outcomes in Patients with Myelodysplastic Syndrome Undergoing Allogeneic Stem Cell Transplantation

Correlations between Pre-Transplant Treatment and Bone Marrow Response with Post-Transplant Outcomes in Patients with Myelodysplastic Syndrome Undergoing Allogeneic Stem Cell Transplantation

Does Presence of Persistent Molecular Mutations Matter in AML Patients Undergoing Allogeneic Stem Cell Transplant?

Introduction: Mutations at diagnosis in acute myeloid leukemia (AML) patients have prognostic implications. For AML patients undergoing allogeneic stem cell transplant (SCT), the prognostic impact of molecular mutations pre-transplant and immediately post-transplant are less well characterized. Here we examine the mutation status of AML patients at different time points in relation to allogeneic SCT and their implications in relapse and survival.Methods: AML patients who underwent allogeneic SCT after achieving complete remission with available molecular mutation testing at diagnosis, prior to transplant (within 4 weeks), and 28 days post-transplant were included in the analysis. Multivariable cox regression analysis was adjusted for age, gender, CIBMTR disease risk index (DRI), type of transplant, and genetic mutation. Backward selection method was used to select the best combination of genes that is associated with OS and relapse-free survival (RFS).Results: A total of 110 AML patients with molecular genetic data available from 2014 to2018 at Weill Cornell Medicine were included in the analysis. Clinical characteristics of the patients are summarized in Table 1. The median age was 58 years (20-77). Twenty-three molecular mutations analyzed at baseline, pre-transplant, and at 28 days are listed in Table 2.With a median follow-up time of 31.6 month, the median overall survival for the cohort was 37.1 months. Eighty-one patients had molecular testing at diagnosis. The presence of mutations in TP53 at diagnosis was associated with worse OS by both univariate (HR 3.67, p=0.0030, CI 1.56-8.68) and multivariate analysis (HR 4.75, p=0.0014, CI 1.82-12.39) with median OS reduced from 49.3 to 19.3 months (p=0.002). High CIBMTR DRI (HR 0.17, p=0.0018, CI 0.05-0.51) predicted reduced RFS, but not OS on multivariate analysis.Seventy-seven patients had molecular testing prior to transplant and 27 patients had persistent mutations (Table 2). The presence of mutations in ETV6 and FLT3-ITD were independently associated with worse RFS ((HR 49.7, p=0.001, CI 5.0-528) & (HR 36.4, p<0.0001, CI 6.6-200)) and OS ((HR 38.31, p=0.0035, CI 3.31-443.37) & (HR 10.57, p=0.0038, CI 2.14-52.27)). The presence of NRAS mutations was associated with worse RFS (HR 105, p=0.0004, CI 8.1-1350), but not OS. Mutations in TP53 were associated with worse RFS (HR 70.97, p=0.0026 CI 4.44-1135) and OS on univariate (HR 9.82, p=0.0327, CI 1.21-79.82), but not on multivariate analysis.At 28 days post-transplant, only 9 of the 84 patients had persistent mutations. Persistence of FLT3-ITD conferred worse RFS and OS in both univariate ((HR 11.92, p=0.0218, CI 1.43-98.98) & (HR 25.16, p=0.0052, CI 2.62, 241.92)) and multivariate ((HR 18.13, p=0.0089, CI 2.07-158.86) & (HR 35.47, p=0.0028, CI 3.41-368.81)) analysis.Conclusions: Persistent presence of mutations in ETV6 and FLT3-ITD prior to stem cell transplant were associated with shorter RFS and OS independent of CIBMTR DRI. Persistent mutations in NRAS and CBL prior to stem cell transplant were associated with poor RFS and OS respectively. This analysis further supports association of adverse outcomes in AML patients with selected persistent mutations prior to stem cell transplant. Utility of serial mutation testing prior to transplant should be further investigated in prospective studies. [Display omitted] DisclosuresLee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Ritchie:NS Pharma: Research Funding; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; ARIAD Pharmaceuticals: Speakers Bureau; Astellas Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Desai:Argenx: Consultancy; Cellerant Inc: Consultancy. Roboz:Eisai: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Novartis: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Orsenix: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Cellectis: Research Funding; Celltrion: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Argenx: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Sandoz: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Bayer: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy.

Phase 1 First-in-Human Trial of AMV564, a Bivalent Bispecific (2x2) CD33/CD3 T-Cell Engager, in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

▪Background: AMV564 is a novel bivalent, bispecific (2x2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T-cell receptors with strong avidity, thus creating an immune synapse between CD33-expressing cells and T cells, initiating T-cell directed lysis of CD33 expressing cells, and inducing expansion, differentiation and proliferation of T cells. By design, AMV564 has reduced clearance and therefore has a longer half-life (t1/2) than monovalent, bispecific T-cell engagers. In preclinical investigations using both leukemic cell lines and primary cells from AML patients, AMV564 eliminated myeloid blasts with picomolar potency and broad activity independent of cytogenetic or molecular abnormalities, CD33 expression level, and disease stage, with no nonspecific activation of T cells (Reusch U et al. Clin Cancer Res 2016;22:5829-38).Methods: This is an ongoing Phase 1 study with a 3+3 dose-escalation design (NCT03144245). The primary objectives of this study are to characterize the safety, tolerability, and preliminary anti-leukemic activity of AMV564. Evaluation of pharmacokinetics (PK), cytokine changes, and immunophenotyping are secondary objectives. Key inclusion/exclusion criteria are: adults with relapsed and/or refractory AML after 1-2 prior induction regimens (with a standard anthracycline-based regimen or hypomethylating agent) and no more than 2 prior salvage regimens. AMV564 is administered by continuous intravenous infusion (CIV) for 14 consecutive days for up to 2 induction cycles. AMV564 and cytokine (IL2, IL4, IL6, IL8, IL10, TNF-α, and IFN-γ) concentrations were measured by validated immunoassays. T-cell activation was measured using flow cytometry to quantify T cells expressing CD25, CD38, CD69, or HLA-DR.Results: To date, 19 patients (10 male/9 female) with a median age of 72 years (range 24-84) have been enrolled in 6 dosing cohorts: 0.5, 1.5, 5.0, 15, 50, and 100 mcg/day. Thirteen patients (68%) had secondary AML and/or adverse cytogenetics, including 6 patients (32%) with a p53 mutation. Fifteen patients (79%) had received at least 1 prior salvage regimen and 11 (58%) had received prior intensive chemotherapy, including 6 patients (32%) who had received a high-dose (≥ 1 gm/m2) cytarabine-based regimen. Overall, 18 patients were evaluable for toxicity and response. No dose-limiting toxicity or treatment-related grade ≥ 3 adverse events (AE) were reported. Grade 2 CRS was observed in 1 patient (treated at 50 mcg/day) without a lead-in dose and was managed with drug interruption and 1 dose of tocilizumab. The patient was able to resume dosing and completed the full 14-day scheduled therapy without recurrence of CRS. Subsequent patients treated at 50 mcg/day and above were given a 15 mcg/day lead-in dose for 3 days followed by 11 days at the assigned dose level. The most common grade ≥ 3 treatment-emergent AE has been febrile neutropenia, reported in 39% (7/18) of patients and all considered unrelated to study drug. No patient has died within 30 days of treatment initiation. AMV564 PK was linear with a terminal t1/2 of 2-3 days. Plasma concentrations increased gradually, with times to steady-state concentration of 3-7 days. Marked increases in IL6 (peak concentration, 1.1 ng/mL), IL8 (1.5 ng/mL), and IL10 (0.3 ng/mL) cytokines were observed and increased numbers of activated T-cells were detected post-treatment. Reductions in bone marrow blasts, ranging from 13% to 91%, were observed in 12 of 18 evaluable patients including a partial response after cycle 1 in 1 patient at the 100 mcg/day dose level.Conclusions: AMV564 is well-tolerated and demonstrates anti-leukemic activity through T-cell engagement. AMV564 has a unique PK profile with a gradual increase in drug concentration and thus the potential for controlled T-cell activation. DisclosuresRoboz:Daiichi Sankyo: Consultancy; Argenx: Consultancy; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Otsuka: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Astex Pharmaceuticals: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Orsenix: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Orsenix: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Arog: Research Funding. Lee:AstraZeneca: Consultancy; Clinipace: Consultancy; Karyopharm Therapeutics Inc: Consultancy; LAM Therapeutics: Research Funding; Amgen: Consultancy. Rettig:Amphivena Therapeutics: Research Funding; Novimmune: Research Funding. Han:Amphivena Therapeutics, Inc: Employment. Guenot:Amphivena Therapeutics, Inc: Employment. Feldman:Amphivena Therapeutics, Inc: Employment.

Acute Myeloid Leukemia (AML) with Somatic Mutations in PTPN11 Is Associated with Treatment Resistance and Poor Overall Survival

Acute Myeloid Leukemia (AML) with Somatic Mutations in PTPN11 Is Associated with Treatment Resistance and Poor Overall Survival