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964 Lisaftoclax (APG-2575) Safety and Activity As Monotherapy or Combined with Acalabrutinib or Rituximab in Patients (pts) with Treatment-Naïve, Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (R/R CLL/SLL): Initial Data from a Phase 2 Global Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Drugs in Development and COVID-19
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, CLL, Lymphomas, Combination therapy, Diseases, Therapies, Lymphoid Malignancies
Monday, December 12, 2022: 5:15 PM

Matthew S. Davids, MD1, Asher Chanan-Khan, MD2, Boyd Mudenda, MD3*, Larysa Nogaieva, MD4*, Iryna Kriachok, MD5*, Hanna Usenko, MD6*, Vladimir Ivanov, MD7*, Olena Kyselova, MD, PhD8*, Tetiana Perekhrestenko, MD, PhD9*, Ivan Muzhychuk, MD10*, Alexander Myasnikov, MD11*, Zvenyslava Maslyak, MD12*, Andrew Proidakov, MD13*, Olga Uspenskaya, MD14*, Elena Borisenkova, MD15*, Paula Marlton, MD16, Tanya Siddiqi, MD17*, Allison Winter, MD18, Tamila Lysa, MD19*, Bulat Bakirov, MD20*, Lei Fu, PhD3*, Zi Chen21*, Min Yu, MD21*, Mingyu Li, PhD3*, Laura Glass3*, Mohammad Ahmad, MD3*, Olena Karpenko, MD22*, Iurii Osipov, MD23*, Asit De, PhD3*, Ben Paudyal, MD3*, Hengbang Wang, PhD21*, Robert Winkler, MD3*, Nashat Gabrail, MD24*, Vinod Ganju, MD25*, Tatiana S. Konstantinova, MD26*, Olga S. Samoylova, MD27*, Dajun Yang21* and Yifan Zhai3,21

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL
3Ascentage Pharma Group Inc., Rockville, MD
4MI “Cherkasy ROD” of Cherkasy Regional Council, Regional Treatment and Diagnostic Hematology Center, Cherkasy, Ukraine
5Oncohematology department, National Cancer Institute, Ukraine Hemoblastoses of Division of Conservative Methods of Treatment, Kyiv, Ukraine
6Dnipropetrovsk Regional Hematology Center, Dnipro, Ukraine
7Almazov National Medical Research Center, Saint Petersburg, Russian Federation
8Ok Klink, Kyiv, Ukraine
9ARENSIA Exploratory Medicine Unit, Medical Center Named by Academician Yuriy Spizhenko, Kyiv, Ukraine
10SI SP Grygoriev Institute of Radiology of the NAoMS of Ukraine, Kharkiv, Ukraine
11Republican Hospital n.a. V.A. Baranov, St. Petersburg, Russian Federation
12Hematology Department, State Institution "Institute of Blood Pathology and Transfusion Medicine of NAMS of Ukraine", Lviv, Ukraine
13State Institution Komi Republican Oncological Dispensary, Krasnozatonsky, Russian Federation
14Leningrad Regional Clinical Hospital, St. Petersburg, Russian Federation
15Kaluga Regional Clinical Hospital, Kaluga, Russian Federation
16Princess Alexandra Hospital, Brisbane, Australia
17City of Hope Comprehensive Cancer Center, Duarte, CA
18Blood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
19Regional Clinical Hospital n. a. O. F. Herbachevskyi, Zhytomyr, Ukraine
20Bashkir State Medical University, Ufa, Russian Federation
21Ascentage Pharma (Suzhou) Co., Ltd., Suzhou, China
22Ok Klinik, Kyiv, Ukraine
23Almazov National Medical Research Center, St. Petersburg, Russian Federation
24Gabrail Cancer Center, Canton, OH
25PASO Medical, Frankston, Australia
26Regional Clinical Hospital No 1, Ekaterinburg, Russian Federation
27Nizhny Novgorod Regional Clinical Hospital, Named after N. A. Semashko, Nizhniy Novgorod, Russian Federation

Introduction Lisaftoclax, a specific BCL-2 inhibitor, is active in pts with R/R CLL/SLL, including pts whose disease harbored del(17p) and had progressive disease (PD) after Bruton tyrosine kinase inhibitor (BTKi) therapy. This is the first report of lisaftoclax combined with acalabrutinib or rituximab in pts with CLL/SLL (NCT04215809).

Methods Pts with R/R CLL/SLL were treated daily with oral lisaftoclax (400, 600, and 800 mg) alone or combined with continuous acalabrutinib or rituximab for 6 cycles of 28-day cycles. Primary objectives were to determine recommended phase 2 dose (RP2D), safety, and efficacy, including overall response rates (ORRs) of lisaftoclax alone and combined with acalabrutinib or rituximab. Pts underwent lisaftoclax daily ramp-up over 4 to 6 days with monitoring of tumor lysis syndrome (TLS) as follows: Day 1 (D1) 20 mg; D2 50 mg; D3 100 mg; D4 200 mg; and D5 400 mg. Dose ramp-up was followed by Cycle 1 D1 of lisaftoclax target doses of 400, 600 or 800 mg. Pts in the combination groups completed ramp-up as well as an additional 7 days of lead-in of lisaftoclax at the target dose, before acalabrutinib or rituximab was added on C1D8, and then treated until PD or unacceptable toxicity was observed.

Results As of July 4, 2022, 141 pts were enrolled. Median (range) age was 62 (18-80) years; 98 (70%) were male; ECOG score was 0-1 in 125 (89%) and 2 in 15 (11%). Median number of prior therapies was 2 (1-15). Seventeen (12%) pts had progressed on BTKi (n = 15) and/or after venetoclax (n = 3) therapy. β-2 microglobulin levels > 3.5 mg/L were observed in 94 (67%) pts and lymphadenopathy ≥ 5 cm in 51 (36%). In the combination cohorts (n = 95), TP53 mutation or del(17p) was seen in 39 (41%) pts, del(11q) in 27 (28%), unmutated IGHV in 36 (38%), mutated IGHV in 14 (15%), and 47% were unknown. Median exposure to lisaftoclax was 10.0 (0-30) cycles, including 16.5 in the lisaftoclax monotherapy group and 9.0 (1-15) in the rituximab and 7.0 (0-18) in the acalabrutinib combination cohorts. Three (2%) pts with bulky disease met the Cairo-Bishop and Howard criteria for TLS (2 clinical/1 laboratory). Clinical TLS pertained to 1 pt with anuria after first 600 mg dose and 1 pt with grade 1 creatinine increase after second 600 mg dose; both pts fully recovered. A total of 6 pts with bulky disease had transient phosphate levels > 3 mmol/L and/or AST levels > 150 u/L associated with rapid decline in lymphocyte count. Phosphate ≥ 3 mmol/L was managed using binders and/or delayed dose increases. No TLS was observed when acalabrutinib or rituximab was added to lisaftoclax on C1D8. Common (> 5%) any-grade AEs in all cohorts were: neutropenia (30% [26% grade 3/4]); COVID-19 infection (26%); anemia (24% [12% grade 3/4]), diarrhea (20%); thrombocytopenia (17% [5% grade 3/4]), hyperuricemia or pyrexia (9% each); nausea, headache, or fatigue (8% each); increased AST levels (7%); hyperphosphatemia (6%); and increased creatinine (6%). First onset of grade ≥ 3 cytopenias occurred during ramp-up or C1 and rarely after C2 (n = 3 [2%]). Grade ≥ 3 neutropenia was manageable with growth factor support in 13% of pts. No discontinuations were due to lisaftoclax alone or combined with the other agents. Nineteen pts discontinued due to PD (13%), of whom 18 were in the monotherapy group; 4 (3%) pts withdrew consent; 2 (1.4%) had a second primary malignancy; 2 (1.4%) an infection; and 10 (7%) died—8 due to COVID-19 infections as well as 1 multiorgan failure and 1 unknown cause, both unrelated to therapy. No dose-limiting toxicities were observed. Lisaftoclax 600 mg QD was determined as the combination therapy RP2D. No drug-drug interaction was observed in either combination group. Rapid normalization of absolute lymphocyte counts occurred in 56% of pts at the end of daily ramp-up, 58% at the end of C1, and 65% at the end of C2. A total of 43 (65%) ORRs (per 2018 iwCLL criteria) occurred in the monotherapy group, and 53 (98%) and 23 (87%) in the acalabrutinib and rituximab cohorts, respectively. Collection of complete response rate and undetectable minimal residual disease data is in progress.

Conclusions The RP2D of lisaftoclax was 600 mg daily. Initiated with a daily dose ramp-up, lisaftoclax alone or combined with acalabrutinib or rituximab had a manageable safety profile and was active in pts with treatment-naïve or R/R CLL/SLL.

Disclosures: Davids: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ono Pharmaceuticals: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Merck: Consultancy; Eli Lilly and Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Ascentage Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy; Research to Practice: Honoraria; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mudenda: Ascentage Pharma: Current Employment. Marlton: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Siddiqi: Pharmacyclics: Research Funding, Speakers Bureau; Jannsen: Speakers Bureau; Juno Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; BMS: Consultancy; Kite Pharma: Consultancy, Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding; Ascentage Pharm: Research Funding; Beigene: Consultancy, Research Funding, Speakers Bureau; Astrazeneca: Consultancy, Research Funding, Speakers Bureau. Winter: OncLive: Honoraria; Seagen, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fu: Ascentage Pharma: Current Employment. Chen: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company. Yu: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company. Li: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company. Glass: Ascentage Pharma: Current Employment. Ahmad: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company. De: Ascentage Pharma: Current Employment. Paudyal: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company. Wang: Ascentage Pharma: Current Employment. Winkler: Ascentage Pharma: Current Employment. Yang: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company, Other: Leadership, Patents & Royalties. Zhai: Ascentage Pharma: Current Employment, Current equity holder in publicly-traded company, Other: Leadership, Patents & Royalties.

*signifies non-member of ASH