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162 Tuspetinib Myeloid Kinase Inhibitor Safety and Efficacy As Monotherapy and Combined with Venetoclax in Phase 1/2 Trial of Patients with Relapsed or Refractory (R/R) Acute Myeloid Leukemia (AML)

Program: Oral and Poster Abstracts
Type: Oral
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Novel Uses of Approved Therapeutic Agents
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Combination therapy, drug development, Diseases, Therapies, Myeloid Malignancies
Saturday, December 9, 2023: 3:15 PM

Naval Daver, MD1, Kyoo Hyung Lee, MD, PhD2*, Yunsuk Choi, MD, PhD3, Brian A. Jonas, MD, PhD4, Martha Arellano5, Paul B. Koller, MD6, Chul W. Jung, MD7, Sang Kyun Sohn8*, Amir T. Fathi, MD9, Jeong-Ok Lee, MD10, Sung-Soo Yoon, MD, PhD11, Justin M. Watts, MD12, Pankit Vachhani, MD13*, Ho-Jin Shin, MD14*, Jia Hu, PhD15*, Ranjeet Sinha, PhD15*, Nawazish Khan, MD, MS15*, William G. Rice, PhD15 and Rafael Bejar, MD, PhD15

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Asan Medical Center, Seoul, Korea, Republic of (South)
3Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, Republic of (South)
4Department of Internal Medicine, Division of Malignant Hematology, Cellular Therapy and Transplantation, University of California Davis School of Medicine, Sacramento, CA
5Emory University School of Medicine, Atlanta, GA
6Hematology/HCT, City of Hope National Medical Center, Duarte, CA
7Samsung Medical Center, Seoul, KOR
8Kyungpook National University Chilgok Hospital, Daegu, Korea, Republic of (South)
9Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA
10Department of Internal Medicine, Seoul National Univ. Bundang Hospital, Seongnam-Si, None, KOR
11Seoul National University Hospital, Seoul, South Korea
12Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, MIAMI, FL
13O'Neal Comprehensive Cancer Center at the UAB, Birmingham, AL
14Pusan National University Hospital, Busan, Korea, Republic of (South)
15Aptose Biosciences, San Diego, CA

INTRODUCTION: Tuspetinib is a potent once daily oral myeloid kinase inhibitor of SYK, FLT3, JAK1/2, RSK1/2, mutant KIT, and TAK1-TAB1 kinases that mediate dysregulated cellular proliferation in AML. In an orthotopic mouse model of FLT3-mutant AML, tuspetinib exhibited greater antitumor activity than gilteritinib, entospletinib, venetoclax (VEN), and azacitidine (AZA) and combined favorably with VEN and AZA individually. Tuspetinib is being evaluated clinically as monotherapy (TUS) and in combination (VEN/TUS) in a global Phase 1/2 trial of patients with R/R AML.

AIMS: Study objectives are to assess the safety, tolerability, and pharmacokinetics (PK) of TUS and VEN/TUS, to support selection of a recommended phase 2 dose (RP2D).

METHODS: Dose escalation (Part A) and exploration (Part B) of single agent TUS have completed dosing of patients treated at 20 mg to 200 mg once daily. In dose expansion (Part C), 80 mg of TUS is administered continuously as once daily oral monotherapy in 28-day cycles, or in combination with daily VEN with a C1D15 marrow assessment and planned 28-day cycles. Treatment emergent adverse events (TEAE) and clinical responses are evaluated using CTCAE and Revised IWG criteria, respectively.

RESULTS: As of May 30, 2023, 100 patients received TUS in Parts A/B (20mg to 200mg; n=77) and in Part C (n=23: TUS 120 mg (n=14) and TUS 80 mg + VEN 400 mg dose equivalent (n=9)). Patients are predominantly Asian (46%) and White (41%) with a median age of 63 (range 18 to 84); 60% FLT3 wild-type (FLT3-WT), 35% FLT3-mutated (FLT3m) of which 18 (51%) received prior FLT3 inhibitors, and 5% FLT3 undetermined. Patients received a mean of 2.6 prior lines of therapy (range 1-6) (Table 1). Sixty percent of patients have received prior venetoclax.

In Parts A/B, clinical responses with TUS monotherapy (composite complete remission [CRc; including CR, CRh, CRp and CRi]; see Figure 1 for definitions), were observed at 40 mg (15.4%), 80 mg (29.4%), 120 mg (7.1%), and 160 mg (16.7%) in both FLT3-WT (n=33, CRc:15.2%,) and FLT3-mutated (n=23, CRc:21.7%) patients. Overall response rate (ORR, including CRc and PR) was 14.3% in prior VEN treated patients (n=28), 23.1% in FLT3-mutated patients with previous FLT3i treatment (n=13), and 66.7% in NPM1 and FLT3-mutated patients (n=6). Notably, responses were also seen in patients with TP53 (n=5; CRc:40%) and RAS (n=9; CRc:22.2%) mutations frequently associated with resistance to VEN and standard therapies. TUS was well tolerated, with no dose limiting toxicity (DLT) observed at doses ranging from 20 mg to 160 mg. One patient experienced a DLT (Grade 3 muscular weakness) at 200 mg which demonstrated partial improvement at the time of treatment discontinuation (9 days after AE onset). Related TEAEs of Grade ≥3 were low (10.4%) with only neutrophil count decreased and muscular weakness (n=2 each; 2.6%) reported in more than 1 patient. No treatment-related non-hematologic SAEs, deaths, or discontinuations were observed. PK exposure was linear (20 mg-160 mg). The RP2D of 80 mg was selected for TUS monotherapy.

In Part C, all 9 patients receiving VEN/TUS have tolerated treatment to date and remain on study. Eight (89%) patients had prior VEN treatment. Preliminary responses have been observed at the first post-dose bone marrow assessment (C1D15), including patients with prior VEN treatment. No treatment-related SAEs or TEAEs of Grade ≥3 have been reported.

Updated enrollment, safety, PK, and response data will be presented at the meeting along with findings on the association between somatic mutations and TUS sensitivity as well as results for the TUS food-effect absorption study.

CONCLUSIONS: Tuspetinib was well-tolerated and delivered single agent clinical responses across four dose levels among diverse AML genotypes; with a RP2D of 80 mg chosen for future single agent studies. Although early, the VEN/TUS combination has been well tolerated with preliminary objective responses noted.

Disclosures: Daver: Jazz: Consultancy; Pfizer: Consultancy, Research Funding; Shattuck Labs: Consultancy; Agios: Consultancy; Syndax: Consultancy; Trillium: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; ImmunoGen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Trovagene: Research Funding; Novimmune: Research Funding; Glycomimetics: Research Funding; AROG: Consultancy; FATE: Research Funding; Genentech: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Hanmi: Research Funding; Astellas: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Kronos Bio: Research Funding. Jonas: Genentech/Roche: Research Funding; Forty-Seven: Research Funding; Forma: Research Funding; F. Hoffmann-La Roche: Research Funding; Celgene: Research Funding; Aptose: Research Funding; AROG: Research Funding; Amgen: Research Funding; Takeda: Consultancy; Servier: Consultancy; Rigel: Consultancy, Other: travel reimbursement ; Pfizer: Consultancy, Research Funding; Kymera: Consultancy; Jazz: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: protocol steering committee , Research Funding; Gilead: Consultancy, Other: data monitoring committee , Research Funding; Genentech: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BMS: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel reimbursement , Research Funding; Treadwell: Research Funding; Pharmacyclics: Research Funding; Incyte: Research Funding; Sigma Tau: Research Funding; Loxo: Research Funding; Hanmi: Research Funding; Immune-Onc: Research Funding. Koller: treadwell therapuetics: Consultancy, Other: safety review committee; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; takeda: Consultancy, Speakers Bureau. Fathi: Mablytics: Consultancy; Kite: Consultancy; Ipsen: Consultancy; Immunogen: Consultancy; Menarini: Consultancy; Novartis: Consultancy; Orum: Consultancy; Pfizer: Consultancy; PureTech: Consultancy; Remix: Consultancy; Rigel: Consultancy; Servier: Consultancy, Research Funding; Takeda: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Forma: Consultancy; Daiichi Sankyo: Consultancy; Enclear: Consultancy; Celgene: Consultancy, Research Funding; Autolus: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas: Consultancy; Amgen: Consultancy; Agios: Consultancy; AbbVie: Consultancy, Research Funding. Watts: Reven Pharma: Consultancy; Rafael Pharma: Consultancy; Aptose: Consultancy; Takeda: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Servier: Consultancy; Immune Systems Key, Ltd.: Research Funding; Rigel: Consultancy, Research Funding; Attivare: Consultancy. Vachhani: Incyte, CTI BioPharma Corp, Blueprint Medicines: Speakers Bureau; Abbvie, Amgen, Blueprint Medicines, Cogent Biosciences, Incyte, CTI BioPharma Corp, Daiichi Sankyo, GlaxoSmith Kline, Karyopharm, Novartis, Pfizer, Genentech, Inc., Servier, Stemline, MorphoSys, LAVA therapeutics: Honoraria. Hu: Aptose Biosciences: Current Employment. Sinha: Aptose Biosciences: Current Employment. Khan: Aptose Biosciences: Current Employment. Rice: Aptose Biosciences: Current Employment.

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