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1441 Final Results of Phase I/II Study of Selinexor (SEL) with Sorafenib in Patients (pts) with Relapsed and/or Refractory (R/R) FLT3 Mutated Acute Myeloid Leukemia (AML)

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Diseases, AML, Biological, apoptosis, Adult, Therapies, Biological Processes, enzyme inhibitors, Technology and Procedures, Study Population, Clinically relevant, Myeloid Malignancies, NGS, signal transduction
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Naval G. Daver, MD1, Rita Assi, MD1*, Hagop M. Kantarjian, MD2, Jorge E. Cortes, MD1, Farhad Ravandi, MBBS3, Marina Y. Konopleva, MD, PhD1, Tapan M. Kadia, MD2, Gautam Borthakur, MD4, Elias J. Jabbour, MD1, Courtney D. DiNardo, MD, MSc1, Michelle Velasquez, RN1*, Mary Kelly5*, Jing Ning, PhD6*, Graciela M. Nogueras González, MPH7*, Sherry A. Pierce, BSN, BA1*, Dan Gombos, MD8*, Zeev E. Estrov, MD1, Steven M. Kornblau, MD1, Weiguo Zhang, MD, PhD9 and Michael Andreeff, MD, PhD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX
3Department of Leukemia, University of Texas- MD Anderson Cancer Center, Houston, TX
4Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston
6Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston
7Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston
8Department of Ophthalmology, The University of Texas MD Anderson Cancer Center, Houston
9U.T.M.D. Anderson Cancer Center, Houston, TX

Responses to FLT3-inhibitors are usually transient due to emergence of resistance through the acquisition of kinase domain point mutations and other non-mutational mechanisms. SEL is a potent first-in-class Selective Inhibitor of Nuclear Export/SINE™ that exerted marked cell killing of human and murine FLT3-mutant AML cells, including those with ITD, D835Y, ITD+Y842C or ITD+F691L mutations by modulating the cdk inhibitor p27 and anti-apoptotic Mcl-1. The combination of SEL+sorafenib had synergistic pro-apoptotic effects in FLT3-mutated AML cells by suppressing phosphorylation levels of FLT3 and its downstream signaling mediators ERK/AKT, and by inducing myeloid differentiation in ITD and D835 mutated cell lines.

We designed a phase I/II trial of SEL with sorafenib for FLT3-ITD and/or -D835 R/R AML pts. In phase I, the primary objectives were to determine the maximum tolerated dose (MTD), the recommended phase 2 dose (RP2D), and dose-limiting toxicity (DLT) of the combination. In phase II, primary objectives included the rate of composite complete remission (CRc) defined as CR+CR with incomplete platelet recovery (CRp)+CR with incomplete count recovery (CRi) within 3 months (mos) of therapy initiation. Secondary objectives were safety and overall survival (OS). SEL was given orally twice a week for 3-weeks on and 1-week off in 28-day cycles and sorafenib was given continuously at a dose of 400mg twice daily from cycle 1 day 1 of SEL. In phase I, SEL dose was de-escalated in “3+3” fashion starting at dose level 0 and going down if DLTs were exceeded (dose levels 0, -1, -2 = 80, 60, 40 mg, respectively). Once MTD was established, the phase II enrolled pts in 2 cohorts: prior FLT3-inhibitor failure (cohort 1) and FLT3-inhibitor naïve (cohort 2). PB or BM samples were collected at pre-dose (C1D1), 24 h (C1D2) and day 28 (C1D28) of cycle 1, and apoptosis induction was determined by measuring annexin V positivity with FACS.

17 pts with median (med) age of 68 yrs (range 24-81) were enrolled. All pts had baseline next generation sequencing for AML specific mutations (Fig 1A). Median number of prior therapies was 3 (range, 1-6) as follows: salvage (S) 1: n=1, S2: n=7, S3+: n=9. 12 (71%) pts had prior FLT3-inhibitor exposure: 1 prior FLT3-inhibitor (n=10); 2 prior FLT3-inhibitors: n= (2). Four pts had prior allogeneic stem cell transplant.

Four pts were treated at dose level 0 (SEL 80mg) with DLTs in 2 (Grade (G) 3 sepsis, n=1; G3 mucositis, syncope, adrenal insufficiency, n=1). Three pts were subsequently treated at dose level -1 (SEL 60mg) with no DLTs and this was established as the MTD/RP2D. Ten pts were treated in expansion: 7 had prior FLT3-inhibitor therapy (cohort 1) and 3 had no prior FLT3-inhibitor (cohort 2). Med duration of treatment for all 17 pts was 55 days (range 14-122) and all pts are off-protocol. All pts are evaluable for response. Overall, 5 pts (29%) achieved a CRc including CR (1/17; 6%), CRi (2/17, (12%) CRp(2/17; 12%). Interestingly, all responders had prior FLT3 inhibitor exposure (1 prior FLT3i in 3 pts, 2 prior FLT3i in 2 pts) indicating a CRc rate of 45% (5/11) in pts with prior FLT3 inhibitor exposure. Two pts with CRi and 1 with CRp (2 with FLT3-ITD and 1 with ITD+D835) achieved negative RT-PCR for FLT3 at time of response (Fig 1B). Med DOR was 2.6 mos (range 1-6.1). Med OS for all pts on study was 4 mos (range 0.9-16.54) and 16.54 mos for responders (CR/CRi/CRp) (range 2.7-16.54). One pt in CRi was bridged to SCT and remained alive at 1.5 yrs. G 1/2 adverse events (AE) included anorexia (n=8), nausea/vomiting (n=8) and diarrhea (n=4). G 3/4 AE irrespective of causality were bleeding (gastrointestinal n=4; intracranial n=1), febrile neutropenia (n=5), pneumonia (n=3), syncope (n=2), hyponatremia (n=2), weakness (n=1) and fatigue (n=1). Drug related G 3/4 AE were hyponatremia (n=2), mucositis (n=1), adrenal insufficiency (n=1), and fatigue (n=1). The reasons for discontinuing study therapy were disease progression (n=13; 76%), toxicity (n=3; 18% including fatigue, mucositis and sepsis), SCT (n=1; 6%). On translational analysis, SEL+sorafenib induced apoptosis in 4/5 tested pts, especially in BM samples (Fig 1C).

The combination of SEL+sorafenib was safe and clinically active with apoptosis induction in heavily pre-treated R/R FLT3+ AML. The benefit was especially encouraging in pts exposed to prior FLT3 inhibitor, with 45% CR/CRi/CRp rate (5/11; including 1 CR, 2 CRi and 2 CRp). The RP2D is 60 mg twice weekly of SEL

Disclosures: Daver: Karyopharm: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Consultancy, Research Funding; Alexion: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; ARIAD: Research Funding; Sunesis: Consultancy; Pfizer: Research Funding; ImmunoGen: Consultancy, Research Funding; Otsuka: Consultancy. Kantarjian: Pfizer: Honoraria, Research Funding; Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria. Cortes: Arog: Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ravandi: Seattle Genetics: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria. Konopleva: Stemline Therapeutics: Research Funding. Kadia: Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Novartis: Consultancy; BMS: Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; BMS: Research Funding; Abbvie: Consultancy; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding. Jabbour: Abbvie: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding. DiNardo: Agios: Consultancy; Syros: Honoraria; Jazz: Honoraria; Abbvie: Consultancy; Medimmune: Honoraria; Bayer: Honoraria; Celgene: Consultancy; Karyopharm: Honoraria. Andreeff: United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; SentiBio: Equity Ownership; Jazz Pharma: Consultancy; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Equity Ownership; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; Celgene: Consultancy; Reata: Equity Ownership.

*signifies non-member of ASH