A Phase 1 Study of LY3410738, a First-in-Class Covalent Inhibitor of Mutant IDH in Advanced Myeloid Malignancies (Trial in Progress)

Background: Mutations in isocitrate dehydrogenase 1/2 (mIDH) are collectively found in up to 20% of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Reversible inhibitors of IDH1 (ivosidenib) and IDH2 (enasidenib) are currently approved and achieve response rates of ~40%, with median duration of response of <1 year in the approved relapsed AML setting. Among patients who relapse, restoration of the 2-HG oncometabolite may be mediated by IDH second site mutations or isoform switching. LY3410738 is a potent, selective, and covalent inhibitor of IDH1-R132. LY3410738 is differentiated from prior IDH inhibitors by 1) its unique covalent binding mode, 2) its increased potency against IDH1-R132, and 3) its unique binding site outside of the dimer interface, which enables continued potency in the setting of known common second site IDH mutations. This trial will investigate the activity of LY3410738 in patients with hematologic malignancies harboring mIDH. Study Design and Methods: This is an open-label, multicenter, global Phase 1 study of oral LY3410738 in relapsed or refractory (R/R) mIDH myeloid malignancies. Enrollment will begin in patients with IDH1-R132 mutations. Key eligibility criteria (in addition to the IDH-R132 mutation) include at least 18 years of age, diagnosis of AML or high risk MDS or other R/R hematologic malignancy, ECOG PS ≤2, and adequate organ function. Key exclusion criteria include a history of hematopoietic stem cell transplant or CAR-T therapy within 60 days of first LY3410738 dose. Primary objectives of the study are to determine the recommended Phase 2 dose (RP2D) and to assess the preliminary anti-tumor activity of LY3410738 based on overall response rate using modified 2017 ELN recommendations (for AML) or modified IWG Response Criteria (for MDS). Secondary objectives include evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics (expressed by changes in 2-HG levels in plasma). Dose escalation will follow a 3+3 design, allowing for patient backfill to dose levels cleared that are predicted to achieve therapeutic exposures. Each cycle will be 28 days (4 weeks). Once the RP2D is determined, patients will be enrolled into one of 4 dose expansion cohorts based on IDH mutation, myeloid malignancy, and prior therapy, including reversible IDH inhibitors. Cohort 1 will enroll patients with R/R AML harboring an IDH1-R132 mutation who have received standard therapy, including a prior IDH inhibitor. Cohort 2 will enroll patients with R/R AML harboring an IDH1-R132 mutation who have received standard therapy, excluding a prior IDH inhibitor. Cohort 3 will enroll patients with R/R MDS, chronic myelomonocytic leukemia (CMML) or other advanced hematologic malignancy harboring an IDH1-R132 mutation who have received standard therapy. Based on preliminary preclinical activity of LY3410738 in mutant IDH2 assays, Cohort 4 will enroll patients with R/R AML, MDS, CMML, or other advanced hematologic malignancy harboring IDH2 mutations who have received standard therapy. Approximately 80 patients (20 patients per cohort) will be enrolled in the 4 exp cohorts. The study is planned to enroll patients in late 2020. Disclosures Stein: Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Bayer: Research Funding; Abbvie: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Biotheryx: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Konopleva:Genentech: Consultancy, Research Funding; Ascentage: Research Funding; AstraZeneca: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; F. Hoffmann La-Roche: Consultancy, Research Funding; Sanofi: Research Funding; AbbVie: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Ablynx: Research Funding; Kisoji: Consultancy; Eli Lilly: Research Funding; Cellectis: Research Funding; Rafael Pharmaceutical: Research Funding; Amgen: Consultancy; Calithera: Research Funding; Agios: Research Funding; Stemline Therapeutics: Consultancy, Research Funding. Gilmour:Eli Lilly and Company/Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Szpurka:Eli Lilly and Company/Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Hill:Eli Lilly and Company/Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company; Medical University of South Carolina: Ended employment in the past 24 months, Other: grants to institution and honoraria for various activities from NIH, ASCO, AACR. No longer receiving funding or honoraria, Research Funding. Ward:Eli Lilly and Company/Loxo Oncology at Lilly: Consultancy, Current equity holder in publicly-traded company; CTI Biopharma: Consultancy; InClin Inc.: Consultancy; Sunesis Pharmaceuticals, Inc.: Consultancy, Current equity holder in publicly-traded company; Oasis Clinical Inc.: Current Employment, Current equity holder in private company. Kantarjian:BMS: Research Funding; Abbvie: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; BioAscend: Honoraria; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Ascentage: Research Funding; Delta Fly: Honoraria; Amgen: Honoraria, Research Funding. Dinardo:AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria; Agios: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria.

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A Phase 1 Study of NKX019, a CD19 Chimeric Antigen Receptor Natural Killer (CAR NK) Cell Therapy, in Subjects with B-Cell Malignancies

Blood ◽

10.1182/blood-2021-146602 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3868-3868

Author(s):

Michael Dickinson ◽

Nada Hamad ◽

Christian E Bryant ◽

Gautam Borthakur ◽

Chitra Hosing ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Nk Cells ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Publicly Traded ◽

Phase 1 Study ◽

Advisory Committees ◽

Car T

Abstract Background: B-cell lineage cancers are a worldwide healthcare burden. Over 500,000 new cases of non-Hodgkin lymphoma (NHL) and 50,000 new cases of acute lymphoblastic leukemia (ALL) are diagnosed world-wide each year (seer.cancer.gov, Smith 2015, Solomon 2017). Despite progress in treatment, many patients diagnosed with this heterogeneous group of cancers still succumb to their disease. Recently approved autologous chimeric antigen receptor (CAR) T cells specific for CD19 have altered the treatment landscape for some patients with relapsed or refractory (R/R) B-cell malignancies, though significant toxicities associated with T-cell expansion and the necessity for bespoke manufacturing have limited their use. Natural killer (NK) cells, part of the innate immune system, efficiently recognize transformed cells and are particularly suited to address limitations of the approved CAR T products (Marcus 2014, Morvan 2016). Lacking a T-cell receptor and the consequent clonal expansion, non-engineered NK cells have been safely administered after lymphodepletion without side effects typically associated with T-cell therapies, such as severe cytokine release syndrome or neurotoxicity (Bachier 2020). Allogeneic NK cell-based therapies allow off-the-shelf use, obviating the necessity to wait for manufacture of autologous T-cell therapies. CD19-directed CAR NK cells have been administered safely, with promising preliminary efficacy (Liu 2020). NKX019 is a cryopreserved product, composed of expanded NK cells engineered to express a humanized CAR against CD19, fused to co-stimulatory (OX40) and signaling (CD3ζ) domains to enhance their intrinsic antitumor activity. NKX019 also expresses a membrane-bound interleukin-15 (IL-15) to serve as an autocrine growth factor and thereby increase NKX019 persistence, with an in vivo half-life of over up to 28 days without systemic IL-2 support. Preclinical characterization has shown that NKX019 cells are 10 times more effective at killing CD19+ target cells than non-engineered NK cells, resulting in greater suppression of xenograft tumor models (Morisot 2020). Further, NKX019, unlike CD19 CAR T cells, retained cytotoxicity even when CD19 antigen density was reduced >50x on target cells. Hence, clinical evaluation of NKX019 is being undertaken in this Phase 1 study in subjects with R/R NHL or ALL. Methods: This is a multicenter, open-label, Phase 1 study of NKX019 (Figure). The study will be conducted in 2 parts: Part 1 (dose finding) to determine the recommended Phase 2 dose (RP2D) of NKX019 separately in adult patients with CAR T naïve R/R NHL or B-ALL, utilizing a "3+3" enrollment schema. Part 2 (dose expansion) will further evaluate safety and tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PDn), and antitumor activity of NKX019 using RP2D with separate expansion cohorts for patients with ALL as well as different subtypes of NHL, including a cohort of CAR T pretreated large B-cell lymphoma. NKX019 is being manufactured from NK cells obtained from healthy adult donors. The study evaluates two dose levels of NKX019: 3 × 10 8 and 1 × 10 9 viable CAR+ NK cells. NKX019 will be administered on Days 0, 7, and 14 of a 28-day cycle following standard fludarabine/cyclophosphamide lymphodepletion (Table). Up to 5 total cycles may be administered based on response and tolerability assessed at the end of each cycle. The primary endpoint is incidence of adverse events, dose-limiting toxicities, clinically significant laboratory abnormalities, and determination of the RP2D. Secondary endpoints include evaluation of standard cellular PK parameters, PDn, immunogenicity, and antitumor responses. Subjects will be assessed for efficacy using disease-specific criteria: Lugano classification with LYRIC refinement for pseudo-progression (NHL), 2018 International Workshop (IW) criteria (CLL), 6th IW criteria (Waldenström macroglobulinemia [WM]), and National Comprehensive Cancer Version 1.2020 (B-ALL) (Cheson 2006, Cheson 2014, Hallek 2018, Owen 2013, Brown 2020). Enrollment across multiple sites in the US and Australia is expected to start in the second half of 2021. Figure 1 Figure 1. Disclosures Dickinson: Celgene: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bryant: Jansen, BMS/Celgene, Skyline Diagnostics: Consultancy; Amgen: Honoraria. Borthakur: Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Ryvu: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Shook: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tan: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Rajangam: Nkarta Therapeutics: Current Employment, Current equity holder in publicly-traded company. Liu: SITC: Honoraria; BMS; Karyopharm; Miltenyi: Research Funding; Agios; NGM Biopharmaceuticals; BeiGene: Consultancy. McSweeney: Kite-Gilead: Consultancy; Kite-Gilead, Autolus, Novartis: Research Funding; Kite-Gilead: Honoraria, Speakers Bureau. Hill: Novartis: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AstraZenica: Consultancy, Honoraria; Beigene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding.

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A First-in-Human Phase 1 Study of Oral LOXO-338, a Selective BCL2 Inhibitor, in Patients with Advanced Hematologic Malignancies (Trial in Progress)

Blood ◽

10.1182/blood-2021-145380 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2424-2424

Author(s):

Alvaro J. Alencar ◽

Lindsey E. Roeker ◽

Marc Hoffmann ◽

Guru Subramanian Guru Murthy ◽

Vishalkumar Patel ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Standard Therapy ◽

Research Funding ◽

Phase 1 ◽

Hematologic Malignancies ◽

Publicly Traded ◽

Advisory Committees ◽

Molecule Inhibitor ◽

Orally Bioavailable

Abstract Background: B-cell lymphoma 2 (BCL2) is a key regulator of apoptosis and provides protection from cell death in many hematological malignancies. The BCL2 inhibitor venetoclax is approved for the treatment of CLL/SLL and acute myeloid leukemia and has activity in other lymphoid malignancies. LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL2, designed to achieve selectivity over BCL-xL and thus avoid dose-limiting thrombocytopenia associated with BCL-xL inhibition. In preclinical studies, LOXO-338 showed a favorable pharmacological profile, selectively inhibited BCL2, and was well-tolerated in vivo. LOXO-338 also demonstrated dose-dependent tumor growth inhibition in various murine xenograft models, and showed improved efficacy in combination with pirtobrutinib, a highly selective, non-covalent BTK inhibitor (Brandhuber et al. Cancer Res 2021; 81, 13 Supplement, 1258). Study Design and Methods: LOXO-BCL-20001 is an open-label, multi-center, first-in-human Phase 1 study of oral LOXO-338 in patients with advanced hematologic malignancies who have received standard therapy. The study will be conducted in 2 parts. Part 1 will evaluate LOXO-338 as monotherapy, and will explore different dosing strategies. Part 2 will evaluate LOXO-338 in combination with pirtobrutinib. The dose escalation portion of the study in Part 1 will follow an i3+3 design. Each cycle will be 28 days (4 weeks). Eligible patients include those with CLL/SLL, mantle cell lymphoma (MCL), and Waldenstrӧm macroglobulinemia (WM) who have already received standard therapy. Patients with other B-cell non-Hodgkin lymphomas (NHLs) who failed standard therapy or, in the opinion of the investigator, have no known available options to provide benefit for the patient's condition, are also eligible. Patients must have recovered from prior treatment-related adverse events. Patients with active or suspected Richter transformation, transformed low grade lymphoma, Burkitt or Burkitt-like lymphoma, and multiple myeloma (MM) are eligible in dose-expansion. Key exclusion criteria include history of CNS involvement, stem cell transplant or CAR-T therapy <60 days, concurrent anticancer therapy, and clinically significant cardiovascular disease. The primary objective of Part 1 is to determine the maximum tolerated dose (MTD)/ recommended Phase 2 dose (RP2D) of oral LOXO-338 in patients who were previously treated for CLL/SLL and other B-cell NHLs. Key secondary objectives include determining the safety and tolerability, and pharmacokinetic properties of LOXO-338. Antitumor activity will be evaluated based on overall response rate (ORR), progression-free survival (PFS), time to progression (TTP) and duration of response (DOR) based on disease-specific response criteria per investigator assessment. Key objectives of part 2 are to determine the safety profile and tolerability, PK properties, and anti-tumor activity of LOXO-338 in combination with pirtobrutinib. Disclosures Alencar: Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Epizyme: Consultancy; Celgene: Consultancy; BeiGene: Consultancy; Amgen: Consultancy. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy, Research Funding; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company. Hoffmann: TG Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmcyclics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria. Guru Murthy: Cancerexpertnow: Honoraria; Guidepoint: Consultancy; Techspert: Consultancy; Qessential: Consultancy; Cardinal Health Inc.: Honoraria; TG therapeutics: Other: Advisory board. Patel: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Ku: Loxo Oncology at Lilly: Current Employment, Current holder of stock options in a privately-held company. Pauff: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Eyre: Incyte: Consultancy; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Janssen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding. Jurczak: Celtrion: Research Funding; Celgene: Research Funding; Debbiopharm: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. OffLabel Disclosure: LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL2 for advanced hematologic malignancies.

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Pharmacokinetic / Pharmacodynamic (PK/PD) Simulations Guide Selection of the Dose for Administration of Efgartigimod Subcutaneously in a Phase 3 Clinical Trial in Patients with Primary Immune Thrombocytopenia

Blood ◽

10.1182/blood-2021-153261 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3165-3165

Author(s):

Waleed Ghanima ◽

Vickie McDonald ◽

Shivi Jain ◽

Monica Carpenedo ◽

Esther N. Oliva ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Immune Thrombocytopenia ◽

Phase 1 ◽

Advisory Board ◽

Phase 2 ◽

Publicly Traded ◽

Phase 1 Study ◽

Phase 3 ◽

Advisory Committees

Abstract Introduction Efgartigimod (ARGX-113) is a human IgG1-derived Fc fragment that binds with high affinity to FcRn in a pH dependent way, resulting in a blockade of FcRn-mediated recycling of IgGs. This leads to rapid degradation of all IgGs, including disease associated autoantibodies. The efficacy, safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profile of intravenously (IV) administered efgartigimod have been assessed during a Phase 1 study in healthy subjects (Ulrichts P. JCI. 2018;128), Phase 2 studies in patients with Myasthenia gravis (MG) (Howard JF. Neurol. 2019;92) and Immune Thrombocytopenia (ITP) (Newland AC. Am J Hematol. 2020;95:178-187), and a Phase 3 study in MG (Howard JF. Lancet Neurol. 2021;20). These studies have demonstrated that a dose of 10 mg/kg efgartigimod, administered in four weekly (qw) IV infusions, achieves close to maximal immunoglobulin G (IgG) reduction and a significant reduction of pathogenic autoantibodies in patients with ITP and MG. Furthermore, this dose was well-tolerated in all populations. Based on the results of the Phase 2 study in Primary ITP, a Phase 3 study was designed for IV administration in patients with persistent or chronic primary ITP (ADVANCE NCT04188379). To allow for a convenient SC administration of efgartigimod at a dose that achieves a similar PD effect comparable to IV 10 mg/kg, a co-formulation with rHuPH20 SC was developed (recombinant human hyaluronidase PH20, an enzyme used to increase the dispersion and absorption of co-administered substances when administered subcutaneously). Here we describe the dose selection process for the SC dose to be used in a Phase 3 study of patients with persistent or chronic ITP. Methods PK and PD data from a Phase 1 study, including 32 healthy adult male subjects receiving 750 mg, 1250 mg, 1750 mg, or 10 mg/kg single SC injections of efgartigimod co-mixed with rHuPH20 (8 subjects/dose group), were used for a PK/PD analysis to predict the efgartigimod PH20 SC dose that would result in a similar PD effect compared to the benchmark dose from previous studies of 10 mg/kg IV (1 hour infusion and body weight of 70 kg). Results Weekly SC administration of 1000 mg efgartigimod co-mixed with 2000 U/mL rHuPH20 was predicted to result in comparable maximum total IgG reduction after the 4 th SC injection (days 22-29) as after the 4 th IV infusion of 10 mg/kg administered qw (Figure 1). Additionally, the area under the curve for total IgG concentration after the 4th dose (days 22-29) and trough IgG reduction (measured prior to dose on day 29) were predicted to be comparable between weekly 1000 mg SC and the weekly 10 mg/kg IV benchmark dose. No statistically significant effect of body weight on the PK and PD of efgartigimod PH20 SC was found. Discussion These results informed the weekly SC dose administration schedule in ADVANCE SC, a Phase 3, multicenter, randomized, double-blinded, placebo-controlled trial (NCT04687072) for evaluation of efficacy and safety of efgartigimod PH20 SC in adults with persistent or chronic primary ITP. Efgartigimod PH20 SC or placebo PH20 SC will be given weekly on visits 1-4 and then either weekly or every other week from visits 5 to 16, as determined by platelet counts. The frequency of administration will remain unchanged for the last 7 weeks (visits 17 to 24) to evaluate the sustainable platelet count improvement as the primary objective. Secondary objectives include extent of disease control (overall platelet count response, use of rescue treatment, and changes in concurrent ITP therapy), bleeding events, and quality of life assessments. ADVANCE SC recruitment is currently ongoing across approximately 70 sites in Asia-Pacific, Europe, Japan, Latin America, Middle East, Africa, and USA. Figure 1 Figure 1. Disclosures Ghanima: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Principia: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Research Funding; Pfizer: Research Funding. McDonald: Bayer, Sobi, Novartis, Amgen, argenx: Honoraria; Grifols: Research Funding. Jain: GBT: Speakers Bureau; Novartis: Speakers Bureau; Argenx: Other: advisory board; Sanofi: Other: advisory board; DOVA: Other: advisory board. Oliva: Novartis, Celgene, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Daiichi: Consultancy; Alexion, argenx, Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hultberg: argenx: Current Employment, Patents & Royalties. Gandini: argenx: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Hofman: argenx: Current Employment. Van Bragt: Curare Consulting BV: Other: Partner; argenx: Consultancy. Parys: argenx: Current Employment. van Hoorick: argenx: Current Employment. Miyakawa: Sanofi: Consultancy; Zenyaku Kogyo: Consultancy; Sanofi: Research Funding; argenx: Consultancy, Research Funding. Broome: Alexion, argenx, Apellis, Sanofi: Honoraria.

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Aspacytarabine (BST-236) Is Safe and Efficacious As a Single-Agent, First-Line Therapy for Patients with Acute Myeloid Leukemia Unfit for Standard Chemotherapy. Integrated Results from a Phase 1/2a and an Ongoing Phase 2b

Blood ◽

10.1182/blood-2019-124330 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 179-179

Author(s):

Jessica K. Altman ◽

Tsila Zuckerman ◽

Olga Frankfurt ◽

Selina M. Luger ◽

Dale L. Bixby ◽

...

Keyword(s):

Board Of Directors ◽

Standard Therapy ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Prior Exposure ◽

Efficacy And Safety ◽

First Line ◽

Advisory Committees ◽

Ongoing Phase

Introduction: Aspacytarabine (BST-236) is a prodrug of cytarabine, a backbone of acute myeloid leukemia (AML) therapy. Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Data from a completed phase 1/2a and an ongoing phase 2b studies in AML patients unfit for standard therapy, including patients with AML secondary to therapy and myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA), demonstrate promising single-agent efficacy and safety of aspacytarabine as a potential first-line AML treatment for this challenging population. Aims: To evaluate the efficacy and safety of aspacytarabine in AML patients unfit for standard induction therapy. Methods: A completed phase 1/2a study and an ongoing phase 2b study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The phase 1/2a, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts. The ongoing multi-center phase 2b study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the phase 2b study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions. Results: To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Overall, 25 patients completed 1 course of aspacytarabine, 4 patients completed 2 courses, 1 patient completed 3 courses, and 1 patient completed 4 courses of aspacytarabine. Three patients (in the phase 1/2a study) did not complete the first course. Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological "on-target" events with no drug-related mucositis or cerebellar toxicity. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively. Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy (Table 1). Duration of response and overall survival follow up is ongoing and will be presented at the meeting. Conclusions: The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy. Disclosures Altman: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; Novartis: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Luger:Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria. Kota:Takeda: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Flaishon:BioSight Ltd.: Employment. Tessler:BioSight Ltd.: Employment. Gengrinovitch:BioSight Ltd.: Employment. Ben Yakar:BioSight Ltd.: Employment. Rowe:BioSight: Consultancy.

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A Phase 1 Study of Sea-CD70 in Myeloid Malignancies

Blood ◽

10.1182/blood-2020-136203 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Ahmed Aribi ◽

Anjali S Advani ◽

William Donnellan ◽

Amir T. Fathi ◽

Marcello Rotta ◽

...

Keyword(s):

Board Of Directors ◽

Immune Evasion ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Steering Committee ◽

Advisory Board ◽

Open Label ◽

Advisory Committees ◽

Myeloid Malignancies

Background SEA-CD70 is being developed in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Current treatment options are limited for patients (pts) with relapsed or refractory (r/r) MDS or r/r AML and outcomes remain poor. SEA-CD70 is an investigational humanized, non-fucosylated monoclonal antibody targeting CD70. Expression of CD70 is limited in normal tissue, but is aberrantly expressed on malignant myeloid blasts while absent from healthy hematopoietic progenitor cells. CD70 and its ligand, CD27, may play a role in malignant blast cell survival and/or tumor immune evasion. SEA-CD70 uses a novel sugar-engineered antibody (SEA) platform to produce a non-fucosylated antibody with enhanced effector function. The proposed mechanism of action of SEA-CD70 includes elimination of CD70 positive cells via enhanced antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and mediation of complement-dependent cytoxicity (CDC). Additionally, SEA-CD70 has the potential to block the interaction of CD70 with CD27, which may disrupt signals that enhance blast proliferation and survival and may modulate the immune system to limit immune evasion and increase antigen specific T cell responses. Methods SGNS70-101 is a phase 1, open-label, multicenter, dose-escalation, and cohort expansion study designed to establish the safety, tolerability, and preliminary activity of SEA-CD70 in pts with myeloid malignancies (NCT04227847). Dose escalation is ongoing. In dose escalation, pts must have r/r MDS with 5-20% blasts which has failed prior treatment with a hypomethylating agent (HMA), and have no other therapeutic options known to provide clinical benefit for MDS. After conclusion of dose escalation, monotherapy expansion cohorts will be opened for pts with MDS and for pts with AML. Primary objectives are to evaluate the safety and tolerability, and to determine the maximum tolerated dose (MTD) or recommended expansion dose of SEA-CD70. Secondary objectives are to assess antitumor activity, PK, and immunogenicity of SEA-CD70. Once dose escalation is complete and the recommended monotherapy dose is identified, combination cohorts will be considered in AML and MDS. The study is currently enrolling with sites opening in the US and EU. Disclosures Aribi: Seattle Genetics: Consultancy. Advani:OBI: Research Funding; Takeda: Research Funding; Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Donnellan:Kite Pharma/Gilead: Research Funding; Janssen: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Research Funding; Astex Pharmaceuticals: Research Funding; Incyte: Research Funding; MedImmune: Research Funding; TCR2 Therapeutics: Research Funding; Genentech: Research Funding; PTC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Research Funding; Bellicum Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Celularity: Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Takeda: Research Funding; H3 Biomedicine: Research Funding; Ryvu Therapeutics: Research Funding; Seattle Genetics: Consultancy, Research Funding. Fathi:Astellas: Consultancy; Agios: Consultancy, Research Funding; Amphivena: Consultancy, Honoraria; AbbVie: Consultancy; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy; Jazz: Consultancy, Honoraria; Kite: Consultancy, Honoraria; NewLink Genetics: Consultancy, Honoraria; Novartis: Consultancy; PTC Therapeutics: Consultancy; Takeda: Consultancy; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Kura: Consultancy; Trillium: Consultancy; Seattle Genetics: Consultancy, Research Funding. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Vachani:Blueprint: Consultancy; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Abbvie: Consultancy. Yang:AROG: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding; AstraZeneca: Research Funding. Ho:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Garcia-Manero:Novartis: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; H3 Biomedicine: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Phase 1 Study of Tabalumab, a Human Anti-BAFF Antibody and Bortezomib in Patients with Previously-Treated Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.447.447 ◽

2012 ◽

Vol 120 (21) ◽

pp. 447-447 ◽

Cited By ~ 6

Author(s):

Noopur Raje ◽

Edward Anthony Faber ◽

Paul G. Richardson ◽

Gary J. Schiller ◽

Raymond J. Hohl ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Median Number ◽

Phase 1 Study ◽

Advisory Committees ◽

Baseline Serum ◽

Lower Baseline ◽

Previously Treated

Abstract Abstract 447 Background: Tabalumab, a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF), has demonstrated both anti-myeloma activity and osteoclastogenesis inhibition in xenograft models of multiple myeloma (MM). We initially conducted a Phase 1 study with the combination of tabalumab and bortezomib in previously-treated MM patients who were not refractory to bortezomib. The results from the dose escalation (Part A) have been previously reported, where a tabalumab dose of 100 mg was selected based on several factors, most notably the stabilization of the peak to trough concentration ratio. The cohort expansion (Part B) has since completed enrollment, and we now report the preliminary results for the entire study. Methods: The primary objective was to identify a safe and potentially efficacious dose of tabalumab to be combined with bortezomib. Bortezomib was given in a standard biweekly fashion, 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle, and tabalumab at 1, 10, 30, 100, or 300 mg (Part A) or 100 mg (Part B) IV (30 min) on day 1 in Cycles 1 – 3, 5, and 7. The study was later amended to include dexamethasone to assess safety, and 12 patients received dexamethasone in combination with bortezomib and tabalumab. Response was assessed per IMWG criteria and adverse events per CTCAE v3.0. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were obtained throughout the study, including BAFF, IL-1beta, IL-6, IL-10, VEGF, and TNF-alpha. Results: Forty-eight patients were enrolled to the study; 20 to dose escalation (Part A) and 28 to cohort expansion (Part B). The median age was 65.7 years and 56% were women. The median number of prior therapies was 3 (range 1–10). All patients received either bortezomib or an IMiD; 75% received prior bortezomib and 88% received prior IMiD therapy. The median number of cycles was 5.5 (range 1–28). Grade 3/4 toxicities occurring in two or more patients included peripheral sensory neuropathy, pneumonia, thrombocytopenia, neutropenia, diarrhea, musculoskeletal pain, renal failure acute, fatigue, anemia, neuralgia, and gastrointestinal hemorrhage. Most patients discontinued treatment due to progressive disease or adverse events (neuropathy, neuralgia, fatigue, and thrombocytopenia). Two patients died during study participation - one during treatment from acute respiratory distress syndrome and another during follow-up from multiple myeloma. Confirmed responses included 2 complete responses, 4 very good partial responses, and 16 partial responses. Response associated with lower baseline serum BAFF or IL-6 levels, independent of the tabalumab dose. Also, response in patients treated with tabalumab 100 mg appeared to associate with lower baseline serum levels of IL-10 and undetectable TNF-alpha. With 14 patients censored, the TTP was 4.9 months (95% CI: 4 – 8). With 6 patients censored, the median response duration was 7.3 months (95% CI: 3.5 – 13.9). Conclusions: A 100 mg dose of tabalumab in combination with bortezomib was well tolerated; 22 patients achieved a PR or better despite prior bortezomib and/or IMiD therapy. Response correlated with lower baseline serum BAFF levels, supporting the hypothesis that a higher dose of tabalumab should be evaluated. A three-arm study randomizing patients to the combination(s) of bortezomib, dexamethasone, and tabalumab 100 mg vs. tabalumab 300mg vs. placebo is currently enrolling. Disclosures: Raje: Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Schiller:Eli Lilly & Company: Research Funding. Cohen:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carpenter:Eli Lilly & Company: Employment. Cronier:Eli Lilly and Company: Employment. Kaiser:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

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Preliminary Results from a Phase 1 Study of APVO436, a Novel Anti-CD123 x Anti-CD3 Bispecific Molecule, in Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽

10.1182/blood-2020-141619 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-12

Author(s):

Justin M. Watts ◽

Tara Lin ◽

Eunice S. Wang ◽

Alice S. Mims ◽

Elizabeth H. Cull ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Phase 1 ◽

Cytokine Release ◽

Publicly Traded ◽

Advisory Committees ◽

Acute Myeloid

Introduction Immunotherapy offers the promise of a new paradigm for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). CD123, the IL-3 receptor alpha-chain, represents an attractive target for antibody therapies because of its high expression on AML/MDS blasts and leukemic stem cells compared to normal hematopoietic stem and progenitor cells. APVO436, a novel bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule, depleted CD123+ cells in AML patient samples ex vivo (Godwin et al. ASH 2017), reduced leukemia engraftment in a systemic AML xenograft model (Comeau et al. AACR 2018), and transiently reduced peripheral CD123+ cells in non-human primates with minimal cytokine release and in a dose-dependent fashion (Comeau et al. AACR 2019). These data provide a basis for the clinical application of APVO436 as a treatment in AML and MDS. Here, we report preliminary data from a first-in-human dose-escalation study of APVO436 in patients with R/R AML and high-risk MDS. Study Design/Methods This ongoing Phase 1/1b study (ClinicalTrials.gov: NCT03647800) was initiated to determine the safety, immunogenicity, pharmacokinetics, pharmacodynamics, and clinical activity of APVO436 as a single agent. Major inclusion criteria were: R/R AML with no other standard treatment option available, R/R MDS with > 5% marrow blasts or any peripheral blasts and failure of a hypomethylating agent, ECOG performance status ≤ 2, life expectancy > 2 months, white blood cells ≤ 25,000 cells/mm3, creatinine ≤ 2 x upper limit of normal (ULN), INR and PTT < 1.5 x ULN and alanine aminotransferase < 3 x ULN. Patients were not restricted from treatment due to cytogenetic or mutational status. Intravenous doses of APVO436 were administered weekly for up to six 28-day cycles (24 doses) with the option to continue dosing for up to 36 total cycles (144 doses). Flat and step dosing regimens were escalated using a safety-driven modified 3 + 3 design. Pre-medication with diphenhydramine, acetaminophen, and dexamethasone was administered starting with dose 1 to mitigate infusion related reactions (IRR) and cytokine release syndrome (CRS). First doses and increasing step doses of APVO436 were infused over 20-24 hours followed by an observation period of 24 hours or more. Bone marrow biopsies were performed every other cycle with responses assessed by European Leukemia Net 2017 criteria for AML or International Working Group (IWG) 2006 criteria for MDS. Results The data cut-off for this interim analysis was July 9, 2020. Twenty-eight patients with primary R/R AML (n=19), therapy-related R/R AML (n=3), or high-risk MDS (n=6) have been enrolled and received a cumulative total of 186 doses. The number of doses received per patient ranged from 1 to 43 (mean of 6.4 doses). Most patients discontinued treatment due to progressive disease; however, blast reduction was achieved in 2 patients, with one patient with MDS maintaining a durable response for 11 cycles before progressing. APVO436 was tolerated across all dose regimens in all cohorts tested. The most common adverse events (AEs), regardless of causality, were edema (32%), diarrhea (29%), febrile neutropenia (29%), fever (25%), hypokalemia (25%), IRR (21%), CRS (18%), chills (18%), and fatigue (18%). AEs ≥ Grade 3 occurring in more than one patient were: febrile neutropenia (25%), anemia (18%), hyperglycemia (14%), decreased platelet count (11%), CRS (11%), IRR (7%), and hypertension (7%). After observing a single dose limiting toxicity (DLT) at a flat dose of 9 µg, step dosing was implemented and no DLTs have been observed thereafter. No treatment-related anti-drug antibodies (ADA) were observed. Transient serum cytokine elevations occurred after several reported IRR and CRS events, with IL-6 most consistently elevated. Conclusions Preliminary results indicate that APVO436 is tolerated in patients with R/R AML and MDS at the doses and schedules tested to date, with a manageable safety profile. Dose escalation continues and the results will be updated for this ongoing study. Disclosures Watts: BMS: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Lin:Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding; Celgene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mateon Therapeutics: Research Funding; Jazz: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding. Wang:Abbvie: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; PTC Therapeutics: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau. Mims:Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Agios: Consultancy; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Cull:Aptevo Therapeutics: Research Funding. Patel:Agios: Consultancy; Celgene: Consultancy, Speakers Bureau; DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria. Shami:Aptevo Therapeutics: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Cogle:Aptevo Therapeutics: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Chenault:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Macpherson:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chunyk:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. McMahan:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gross:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Stromatt:Aptevo Therapeutics: Current equity holder in publicly-traded company.

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Cedar Trial in Progress: A First in Human, Phase 1/2 Study of the Correction of a Single Nucleotide Mutation in Autologous HSCs (GPH101) to Convert HbS to HbA for Treating Severe SCD

Blood ◽

10.1182/blood-2021-152892 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1864-1864

Author(s):

Julie Kanter ◽

John F. DiPersio ◽

Patrick Leavey ◽

David C. Shyr ◽

Alexis A Thompson ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Gene Correction ◽

Publicly Traded ◽

Advisory Committees ◽

Hematopoietic Stem ◽

The Past ◽

Adult Hemoglobin

Abstract Background Sickle cell disease (SCD) is a recessive monogenic disease caused by a single point mutation in which glutamic acid replaces valine in Codon 6 of the human beta-globin gene (HBB) leading to the production of abnormal globin chains (HbS) that polymerize and cause erythrocytes to sickle. This results in hemolytic anemia, vaso-occlusion and organ damage, which leads to lifelong complications and early mortality. Allogeneic hematopoietic stem cell transplant (allo-HSCT) is the only known cure for SCD, however, its use is limited by the lack of well-matched donors, need for immunosuppression, risk of graft versus host disease and graft rejection. GPH101 is an investigational, autologous, hematopoietic stem cell (HSC) drug product (DP) designed to correct the SCD mutation in the HBB gene ex vivo using a high fidelity Cas9 (CRISPR associated protein 9) paired with an AAV6 (adeno-associated virus type 6) delivery template, efficiently harnessing the natural homology directed repair (HDR) cellular pathway. This approach has the potential to restore normal adult hemoglobin (HbA) production while simultaneously reducing HbS levels. In preclinical studies, HBB gene correction in SCD donor HSCs resulted in ≥60% of gene-corrected alleles in vitro with minimal off-target effects. Gene corrected cells were successfully differentiated toward the erythroid lineage and produced ≥70% HbA in vitro. Long-term engraftment of gene-corrected HSCs was demonstrated in vivo, following transplant into immunodeficient mice, with multi-lineage allelic gene correction frequencies well above the predicted curative threshold of 20%, with potential of this approach to be equivalent or superior to allo-HSCT. In addition, HSC-based correction in an SCD mouse model led to stable adult hemoglobin production, increased erythrocyte lifespan and reduction in sickling morphology, demonstrating the therapeutic potential of this gene correction platform as a curative approach in SCD. Study Design and Methods CEDAR (NCT04819841) is a first-in-human, open-label, single-dose, multi-site Phase 1/2 clinical trial in participants with severe SCD designed to evaluate safety, efficacy and pharmacodynamics (PD) of GPH101. Approximately 15 adult (18-40 years) and adolescent (12-17 years) participants will be enrolled across 5 sites, with adolescent enrollment proceeding after a favorable assessment of adult safety data by a Safety Monitoring Committee. Participants must have a diagnosis of severe SCD (βS/βS), defined as ≥ 4 severe vaso-occlusive crises (VOCs) in the 2 years prior and/or ≥ 2 episodes of acute chest syndrome (ACS), in 2 years prior with at least 1 episode in the past year. Participants on chronic transfusion therapy may be eligible if required VOC and ACS criteria are met in the 2 years prior to the initiation of transfusions. Key exclusion criteria include availability of a 10/10 human leukocyte antigen-matched sibling donor, or prior receipt of HSCT or gene therapy. After eligibility confirmation including screening for pre-treatment cytogenetic abnormalities, participants will undergo plerixafor mobilization and apheresis, followed by CD34+ cell enrichment and cryopreservation, undertaken locally at each trial site before shipment to a centralized manufacturer for GPH101 production. After GPH101 release, participants will undergo eligibility reconfirmation prior to busulfan conditioning and DP infusion. Safety, efficacy and PD measurements will occur for 2 years post-infusion; a long-term follow up study will be offered to participants for an additional 13 years of monitoring. The primary endpoint for this study is safety, measured by the kinetics of HSC engraftment, transplant related mortality, overall survival and frequency and severity of adverse events. Secondary endpoints will explore efficacy and PD, including levels of globin expression as compared to baseline, gene correction rates, clinical manifestations of SCD (including VOC and ACS), laboratory parameters, complications and organ function. In addition, cerebral hemodynamics and oxygen delivery will be assessed by magnetic resonance techniques. Key exploratory endpoints include evaluation of patient-reported outcomes, erythrocyte function, on-target and off-target editing rates, and change from baseline in select SCD characteristics. Disclosures Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Thompson: Agios Pharmaceuticals: Consultancy; Graphite Bio: Research Funding; Vertex: Research Funding; Beam Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; CRISPR Therapeutics: Research Funding; Global Blood Therapeutics: Current equity holder in publicly-traded company; bluebird bio: Consultancy, Research Funding; Novartis: Research Funding. Porteus: Versant Ventures: Consultancy; CRISPR Therapeutics: Current equity holder in publicly-traded company; Allogene Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Ziopharm: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Intondi: Graphite Bio: Current Employment, Current equity holder in publicly-traded company; Global Blood Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Lahiri: Graphite Bio: Current Employment, Current equity holder in publicly-traded company. Dever: Graphite Bio: Current Employment, Current equity holder in publicly-traded company. Petrusich: bluebird bio: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Graphite Bio: Current Employment, Current equity holder in publicly-traded company. Lehrer-Graiwer: Global Blood Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Graphite Bio: Current Employment, Current equity holder in publicly-traded company.

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Platform Incorporating Patient Navigation, Preparative Guidelines, and Hospital at Home May Improve COVID-19 Outcomes for Patients with Myeloid Malignancies

Blood ◽

10.1182/blood-2021-150610 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3019-3019

Author(s):

Brittany Knick Ragon ◽

Tamara K. Moyo ◽

Ashley Sumrall ◽

Ifeyinwa (IFY) Osunkwo ◽

Kris Blackley ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Active Treatment ◽

Research Funding ◽

Hematologic Malignancy ◽

High Risk Population ◽

Advisory Committees ◽

Risk Population ◽

Myeloid Malignancies ◽

Hospital At Home

Abstract Background: Patients (pts) with malignancies are at increased risk of morbidity and mortality from COVID-19. Among these pts, some of the higher case fatality ratios (CFR) reported are among pts with myeloid malignancies, ranging from 37 to 50% (Mehta V, Cancer Discov 2020; Ferrara F, Leukemia 2020). Levine Cancer Institute (LCI) has a robust hematologic malignancy and cellular therapy program that serves many pts with myeloid malignancies, seeing nearly 100 new diagnoses of acute myeloid leukemia per year. A strategy to mitigate risks associated with COVID-19 was established at LCI in partnership with Atrium Health's (AH) Hospital at Home (HAH). HAH was a system wide platform using telemedicine and home health services to assess and monitor COVID-19 + pts at high risk of complications. To augment HAH for our medically complex cancer pts, a virtual health navigation process involving expertise from across LCI, including a specialized nurse navigation team, was developed to rapidly identify LCI pts + for SARS-CoV-2, monitor them under physician supervision, and escalate care as needed with AH HAH. Along with the navigation platform, data-driven guidelines for detecting, monitoring, and managing LCI pts + for SARS-CoV-2 were swiftly employed across the extensive LCI network. Herein we report on the outcomes for LCI pts with myeloid malignancies + for SARS-CoV-2 and outline the employed risk mitigation strategies and their potential impact on these outcomes. Methods: An automated daily list of LCI pts + for SARS-CoV-2 was provided by AH Information Services. Each pt's chart was reviewed by a nurse navigator for hematologic or oncologic diagnosis, outpatient or inpatient status, and COVID-19 symptoms. Pts without a cancer diagnosis were not assigned a navigator. If hospitalized, a pt was not assigned a navigator; following discharge, if enrolled in HAH, a navigator was assigned. In collaboration with HAH, an algorithm for directing care was utilized (Figure 1). A diagnosis-specific navigator contacted and screened the pt with an assessment tool, which scored pts for surveillance and treatment needs (Table 1). Documentation was forwarded to the primary hematologist/oncologist. Comprehensive guidelines for testing, scheduling, management of + pts, research, and process changes were created, disseminated, and actively updated through LCI's EAPathways. For outcome analysis for pts with myeloid malignancies, pt vital status was updated through data cutoff (7/3/21). Results: From inception on 3/20/20 to 12/2/20, 974 LCI patients were identified as SARS-CoV-2 + and reviewed for nurse navigation. Of the 974 pts, including pts with benign and malignant diagnoses, 488 were navigated. Among all SARS-CoV-2 + LCI pts, 145 (15%) had a hematologic malignancy, including 37 (4%) pts with myeloid malignancies. Characteristics are shown in Table 2. Of the 37 pts, 18 (49%) were navigated. 70% with myeloid malignancies were on active treatment at the time of + test. Nearly 50% of those on active treatment were navigated. 46% were hospitalized with COVID-19, with this being the main reason for no assigned navigator. 24% of hospitalized pts were eventually assigned a navigator. Only 3 pts had undergone allogeneic stem cell transplantation (allo-SCT) with a median time from transplant to detection of SARS-CoV-2 of 9 months (range, 7-23). 2 out of 3 cases post allo-SCT were asymptomatic. No pt died from COVID-19 following allo-SCT. Among the navigated pts with myeloid malignancies, there was no death related to COVID-19. 4 pts, all of whom were hospitalized, died from COVID-19 (N=2, myelodysplastic syndrome with 1 on azacitidine; N=2, myeloproliferative neoplasm, both on hydrea). A CFR of 11% was demonstrated for LCI pts with myeloid malignancies. Conclusions: A multidisciplinary response strategy liaising between AH HAH and LCI followed, assessed, and assisted cancer pts + for SARS-CoV-2. With our embedded nurse navigation team's specialized attention along with enhanced physician oversight and close collaboration with AH HAH, opportunities for care escalation or adjustments in cancer-focused care were promptly identified. In this setting, among the high-risk population of pts with myeloid malignancies, a lower CFR than has been reported was observed. A virtual navigation platform with HAH capabilities is a feasible, safe, and effective way to monitor and care for this high-risk population. Figure 1 Figure 1. Disclosures Moyo: Seattle Genetics: Consultancy. Chai: Cardinal Health: Membership on an entity's Board of Directors or advisory committees. Avalos: JUNO: Membership on an entity's Board of Directors or advisory committees. Grunwald: Amgen: Consultancy; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Stemline: Consultancy; Bristol Myers Squibb: Consultancy; PRIME: Other; Trovagene: Consultancy; Blueprint Medicines: Consultancy; AbbVie: Consultancy; Med Learning Group: Other; Pfizer: Consultancy; Sierra Oncology: Consultancy; Janssen: Research Funding; Incyte: Consultancy, Research Funding; Gilead: Consultancy; MDEdge: Other; PER: Other; Cardinal Health: Consultancy; Karius: Consultancy. Copelan: Amgen: Consultancy.

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Trial in Progress: A Phase I Trial of BTX-A51 in Patients with Relapsed or Refractory AML or High-Risk MDS

Blood ◽

10.1182/blood-2020-142557 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-19

Author(s):

Brian J. Ball ◽

Anthony S. Stein ◽

Gautam Borthakur ◽

Crystal Murray ◽

Karin Kook ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Complete Remission ◽

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Cancer Center ◽

Phase 1 Study ◽

Advisory Committees ◽

Expansion Phase

Background: For patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), low response rates and poor overall survival remain unmet clinical needs. AML cells evade apoptosis through overexpression of antiapoptotic genes and inactivation of p53. The antiapoptotic gene Mcl1 is overexpressed in AML cell lines resistant to venetoclax. Similarly, the sensitivity of AML patients' samples to venetoclax inversely correlates with the presence of a TP53 mutation or low expression of p53. In AML, p53 inactivation more commonly results from overexpression of its negative regulators, Mdmx and Mdm2. BTX-A51 is a novel, oral, direct inhibitor of Casein kinase 1α (CK1α), cyclin dependent kinase 7 (CDK7), and CDK9. CK1α phosphorylates Mdmx and Mdm2 leading to enhanced binding and degradation of p53. CDK7 and CDK9 phosphorylate RNA polymerase II (Pol II) to enable transcriptional initiation and elongation, particularly at large clusters of transcriptional enhancers termed super-enhancers (SE). Preclinical studies have demonstrated that BTX-A51 robustly increased p53 protein levels via CK1a inhibition and Mdm2 downregulation while preferentially decreasing SE transcription of key oncogenes such as Myc andMcl1, enabling selective apoptosis of leukemia cells. The combination of CK1α, CDK7, and CDK9 inhibition was synergistic and prolonged survival in multiple genetic and patient-derived xenograft AML models. Study Design and Methods: This is an open-label, multi-center, first-in-human Phase 1 study evaluating the safety of BTX-A51 in patients with R/R AML or high-risk MDS. The trial will be performed in two phases, a dose escalation (phase 1a) and dose expansion (phase 1b). Phase 1a utilizes a hybrid accelerated titration with single patient cohorts and a Bayesian optimal interval (BOIN) design to assess 8 potential dosing cohorts. The maximum tolerated dose (MTD) will be the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate of 0.3. Up to a maximum of 35 patients will be enrolled in the dose escalation phase of the study at Memorial Sloan Kettering Cancer Center, MD Anderson Cancer Center, and City of Hope Cancer Center. Following determination of the MTD, 15 patients will be enrolled in the dose expansion phase for further evaluation of dose-limiting toxicities (DLTs) and for preliminary evidence of efficacy. BTX-A51 will be dosed 3 weeks on drug, followed by 1 week off drug over a 28-day cycle. For the first cycle, patients will receive tumor lysis syndrome prophylaxis with allopurinol and intravenous fluids and be closely monitored. Key inclusion criteria are age ³ 18 years, R/R AML or R/R high-risk MDS, Eastern Cooperative Oncology Group (ECOG) £ 2 and life expectancy of ³ 6 weeks, and adequate kidney and liver function. Key exclusion criteria are receipt of cancer chemotherapy (other than hydroxyurea) within 2 weeks prior to the start of study drug, transplantation within 3 months prior to screening, active graft-versus-host disease requiring systemic immunosuppressive medications, and a white blood cell count > 20 × 109/L. The primary objective for the Phase 1 study is to determine the MTD and recommended Phase 2 dose (RP2D) of BTX-A51. Secondary objectives include evaluating overall response (complete remission, complete remission with incomplete blood count recovery, and partial remission) according to the European LeukemiaNet (ELN) 2017 criteria (Döhner et al. Blood. 2017), survival (overall survival and event-free survival) and pharmacokinetics. Correlative objectives include determining the changes in SEs and SE-driven expression of antiapoptotic genes by chromatin immunoprecipitation and RNA-sequencing. Recruitment is ongoing and this trial is registered on clinicaltrials.gov: NCT04243785 Disclosures Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Borthakur:BioLine Rx: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; FTC Therapeutics: Consultancy; BioTherix: Consultancy; Curio Science LLC: Consultancy; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Polaris: Research Funding; PTC Therapeutics: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy. Murray:Salamandra: Current Employment. Kook:Salamandra: Current Employment. Chan:BioTheryx: Current Employment. Stein:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Biotheryx: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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