On November 2, 2023 Intensity Therapeutics, Inc. (Nasdaq: INTS), a clinical-stage biotechnology company focused on the discovery and development of proprietary, novel immune-based intratumoral cancer therapies designed to kill tumors and increase immune system recognition of cancers, reported that safety, tolerability and efficacy data from IT-01, the company’s ongoing Phase 1/2 clinical trial of INT230-6, either as a monotherapy or in combination with ipilimumab in patients with relapsed, refractory and metastatic sarcomas, was presented at the Connective Tissue Oncology Society 2023 Annual Meeting being held in Dublin, Ireland from November 1-4, 2023 (Press release, Intensity Therapeutics, NOV 2, 2023, View Source [SID1234636830]). The poster will be displayed for the duration of the Annual Meeting.

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Abstract Title: INTRATUMORAL INT230-6 (CISPLATIN, VINBLASTINE, SHAO) ALONE OR WITH IPILIMUMAB PROLONGED SURVIVAL WITH FAVORABLE SAFETY AND IMMUNE ACTIVATION IN ADULTS WITH REFRACTORY SARCOMAS (NCT 03058289)
Presenter: Christian F. Meyer, M.D., Ph.D., M.S., Johns Hopkins Sydney Kimmel Cancer Center
Abstract Number: 1574238

Copies of the presentation materials are available on Intensity’s website on the publications, papers and posters page.

Christian Frederick Meyer, M.D., Ph.D., M.S., is an Assistant Professor of Oncology at the Sidney Kimmel Cancer Center at Johns Hopkins University. Dr. Meyer is an investigator for Intensity’s Phase 1/2 clinical trial of INT230-6 and the presenter of the data at CTOS. Dr. Meyer has placed a number of his sarcoma patients into the study due to the demonstrated significant survival prolongation effects of INT230-6.

"The data presented at CTOS highlights the true potential of INT230-6 as both a monotherapy or in combination with ipilimumab. INT230-6 showed an extensive increase in overall survival in metastatic patients over expected results for the heavily pretreated and diverse sarcoma population with an increase of nearly 15 months compared to a synthetic control. Approval of INT230-6, a locally delivered therapy, could be a paradigm-changing treatment for metastatic cancers," said Lewis H. Bender, President and Chief Executive Officer of Intensity. "INT230-6 can fully saturate a tumor with cytotoxic agents to begin apoptosis and cause necrosis when delivered intratumorally, resulting in immune activation consisting of dendritic and T-cell influx to the tumor all while maintaining a favorable safety profile. We have begun the preparations for a Phase 3 study of INT230-6 as a monotherapy and look forward to providing updates on the trial in the future."

IT-01, now complete, was an open-label Phase 1/2 study of INT230-6 in adults with locally advanced, unresectable or metastatic solid tumors, including sarcoma. INT230-6 dose was determined by a target injected tumor’s diameter or volume and administered intratumorally once every two weeks for up to 5 doses with regular maintenance treatment either alone or in combination with ipilimumab at 3 mg/kg every three weeks for 4 doses. The primary endpoint was safety and approximately 90% of subjects had low grade adverse events.

Efficacy Data:

When compared to synthetic controls, INT230-6 alone extended survival in refractory soft tissue sarcoma subjects by approximately 14.9 months. Dosing higher amounts of INT230-6 relative to a patient’s presenting total tumor burden showed increased survival when compared to the synthetic control. An INT230-6 dose relative to the presenting tumor burden of ≥ 40% further improved overall survival and the addition of ipilimumab may improve survival further.

Median overall survival of INT230-6 was ~14.9 months longer than a synthetic control that was developed to predict survival of the enrolled sarcoma population.
Median survival of synthetic control was about 6.8 months.
The INT230-6 Disease Control Rate was 93% in subjects who received at least one dose of INT230-6 as monotherapy.
Safety Data:

Data to date indicate that INT230-6 has a favorable safety profile and is well tolerated.

The majority of treatment-emergent adverse events (TEAEs) were grade 1 or 2 primarily localized pain, fatigue, and nausea.
Two monotherapy and one combination subject experienced a grade 3 adverse event (AE)
There were no reported grade 4 or 5 AEs.
About INT230-6

INT230-6, Intensity’s lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity’s proprietary DfuseRx℠ technology platform. The drug is composed of two proven, potent anti-cancer agents, cisplatin and vinblastine, and a penetration enhancer molecule (SHAO) that helps disperse potent cytotoxic drugs throughout tumors for diffusion into cancer cells. These agents remain in the tumor resulting in a favorable safety profile. In addition to local disease control, direct killing of the tumor by INT230-6 releases a bolus of neoantigens specific to the patient’s malignancy, leading to engagement of the immune system and systemic anti-tumor effects. Importantly, these effects are mediated without the immunosuppression of concomitant systemic chemotherapy.

On November 2, 2023 Akeso (9926.HK) reported that its collaboration and licensing partner, Summit Therapeutics Inc. (NASDAQ: SMMT) ("Summit") will present data for the novel, potential first-in-class investigational bispecific antibody, ivonescimab (AK112/SMT112), at the 38th Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) in San Diego, CA (Press release, Akeso Biopharma, NOV 2, 2023, View Source [SID1234636829]). The poster with updated data describing ivonescimab’s mechanism of action will be displayed on Saturday November 4, 2023, from 11:55am to 1:25pm Pacific Time. This mechanism of action of ivonescimab was also presented at the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC (American Association for Cancer Research-National Cancer Institute-European Organization for Research and Treatment of Cancer) Conference on Molecular Targets and Cancer Therapeutics.

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Ivonescimab is a novel, potential first-in-class investigational bispecific antibody combining the effects of immunotherapy via a blockade of PD-1 with the anti-angiogenesis effects associated with blocking VEGF into a single molecule. The poster describes how ivonescimab displays unique cooperative binding to each of its intended targets with higher affinity when in the presence of both PD-1 and VEGF.

This could differentiate ivonescimab as there is potentially higher expression (presence) of both PD-1 and VEGF in tumor tissue and the tumor microenvironment (TME) as compared to normal tissue in the body. Ivonescimab’s tetravalent structure (four binding sites) enables higher avidity (accumulated strength of multiple binding interactions) in the tumor microenvironment with over 18 fold increased binding affinity to PD-1 in the presence of VEGF in vitro, and over 4 times increased binding affinity to VEGF in the presence of PD-1 in vitro. This tetravalent structure, the intentional novel design of the molecule, and bringing these two targets into a single bispecific antibody with cooperative binding qualities have the potential to direct ivonescimab to the tumor tissue versus healthy tissue. The intent of this design is to improve upon previously established efficacy thresholds, in addition to side effects and safety profiles associated with these targets.

The marketing application for one indication of ivonescimab was accepted by the Center for Drug Evaluation (CDE) of the China National Medical Products Administration (NMPA) with priority review. Currently, there are four registrational phase III clinical trials being conducted globally, which include three head-to-head trials with PD-1 monoclonal antibody as the positive control drug, and two international multicenter clinical trials.

Summit has begun its clinical development of ivonescimab in order to establish its efficacy and safety in two proposed NSCLC indications:

Ivonescimab combined with chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with a third-generation EGFR tyrosine kinase inhibitor (TKI) (HARMONi trial)
Ivonescimab combined with chemotherapy in first-line metastatic squamous NSCLC patients (HARMONi-3 trial)
Earlier this year, the first patient was treated in Summit’s license territories in the Phase III HARMONi clinical trial. Summit has opened clinical trial sites in the HARMONi-3 trial and expects to begin dosing patients in the current fiscal quarter.

About Ivonescimab (PD-1/VEGF bispecific antibody)
Ivonescimab is a potential first-in-class investigational PD-1/VEGF bi-specific antibody discovered by Akeso. It combines the effects of immunotherapy via a blockade of PD-1 with the anti-angiogenesis effects associated with blocking VEGF into a single molecule. Ivonescimab is currently engaged in multiple Phase III clinical trials worldwide.

In December 2022, Akeso entered into a collaboration and license agreement for up to US$5 billion with Summit Therapeutics ("Summit"). Akeso out-licensed to Summit exclusive rights to ivonescimab (PD-1/VEGF) for the development and commercialization in the United States, Canada, Europe, and Japan. Akeso will retain development and commercialization rights for the rest of the world including China. Ivonescimab is known as AK112 for Akeso’ R&D code at China and Australia, and as SMT112 for Summit’s license territories.

On November 2, 2023 Ryvu Therapeutics [WSE:RVU], a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported that clinical and preclinical data on RVU120, a selective CDK8/19 inhibitor, will be presented on four posters at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, which is being held on December 9 –12, 2023 in San Diego, California (Press release, Ryvu Therapeutics, NOV 2, 2023, View Source [SID1234636828]).

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"At this year’s ASH (Free ASH Whitepaper) conference, we are pleased to present updated clinical and preclinical data that highlight the potential of RVU120 to address hematologic malignancies," said Hendrik Nogai, M.D., Chief Medical Officer of Ryvu Therapeutics. "RVU120 continues to show single-agent clinical activity in patients with AML and HR-MDS, along with a tolerable safety profile. Notably, several patients achieved a reduction of blasts in the bone marrow including one complete response. We also observed hematologic improvement supporting RVU120’s further development as a treatment for patients with LR-MDS and myelofibrosis. In addition, evidence that RVU120 has cytotoxic and differentiating effects on leukemic stem cells highlight its potential as frontline therapy in AML."

Based on these data and in line with prior guidance, Ryvu’s development plan for RVU120 includes initiation of Phase II studies in AML/HR-MDS as a monotherapy and in combination, in myelofibrosis, and an investigator-initiated trial in LR-MDS. Initiation of Ryvu-sponsored studies in AML is planned in Q4 2023, and in the LR-MDS and myelofibrosis studies in H1 2024.

"Our internal Clinical Committee and a global network of external experts have thoroughly assessed the clinical and preclinical results of RVU120, and have recognized its significant potential in the treatment of multiple hematological diseases. This recognition is a crucial element in the recently presented RVU120 development plans," added Hendrik Nogai.

Details on the poster presentations are as follows:

Abstract Title: "Safety and Efficacy Results from CLI120-001 a Phase 1 Study in RR-AML and HR-MDS: Update from Higher Dose Levels"
Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Session date and time: Sunday, December 10, 2023, 6:00 PM – 8:00 PM PST
Poster Number: 2913

Updated higher dose level Phase I data on RVU120 in patients with relapsed/refractory (r/r) acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) demonstrate clinical activity with a tolerable safety profile. 12 of 24 evaluable patients showed clinically relevant benefit, including four blast reductions to <5% in the bone marrow: one complete response and three marrow complete responses in patients with HR-MDS. Three additional patients treated across different dose levels experienced a sustained BM blast reduction, and five patients achieved hematologic improvements. Dose-escalation data continues to demonstrate relevant target inhibition at doses of 110 mg and higher.

Abstract Title: "Preclinical and Clinical Evidence for Erythroid-Stimulating Activity of RVU120 CDK8/19 Inhibitor in AML and MDS"
Session Name: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster II
Session date and time: Sunday, December 10, 2023, 6:00 PM – 8:00 PM PST
Poster Number: 2800

RVU120-induced erythroid differentiation was studied in primary malignant stem cells from MDS patients and in a stem cell model. To date, erythroid improvement has been observed in five evaluable patients in the ongoing Phase Ib study. Bulk RNA-seq analysis confirmed broad transcriptomic changes in the bone marrow (BM) of selected patients after treatment compared to the pre-dose baseline levels. Robust induction of genes involved in erythroblast differentiation and hemoglobin metabolism genes were observed in two AML with myelodysplasia-related changes (AML-MRC) and two AML patients. These clinical and preclinical data strongly support the further development of RVU120 as a novel agent for patients with LR-MDS who are transfusion-dependent and failing first-line therapy.

Abstract Title: "Targeting CDK8/CDK19 to Disrupt Leukemic Stem Cell-like Population in Acute Myeloid Leukemia: Exploring RVU120 As a Promising Frontline Therapy"
Session Name: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Poster III
Session date and time: Monday, December 11, 2023, 6:00 PM – 8:00 PM PST
Poster Number: 4175

Leukemic stem cells (LSC) are a small subset of AML cells that can resist therapy and cause relapse. To achieve a cure for patients, it is essential to eliminate LSCs. In preclinical models, RVU120 displayed cytotoxic and differentiating effects on well-characterized LSC populations. Single-cell studies further revealed RVU120’s ability to inhibit LSC-enriched populations and induce differentiation. In summary, RVU120 emerges as a frontline candidate in AML treatment, addressing therapeutic failures caused by persistent LSCs.

Abstract Title: "Novel Clinically Useful Inhibitor of Mediator Complex, RVU120, Relieves Differentiation Block in MDS/AML"
Session Name: 636. Myelodysplastic Syndromes—Basic and Translational: Poster II
Session date and time: Sunday, December 10, 2023, 6:00 PM – 8:00 PM PST
Poster Number: 3225

Data demonstrate the potential of inhibiting overexpressed mediator complex proteins, including CDK8, to address differentiation blocks and resulting anemias in MDS/AML. Treatment of primary cells in bone marrow collected from MDS and AML patients with RVU120 led to increased erythroid differentiation, as evidenced by changes in the expression of erythroid differentiation markers, including increased CD71 and Glycophorin A expression. These studies provide supportive evidence for RVU120 as a drug candidate in transfusion-dependent MDS/AML patients.

On November 2, 2023 TC BioPharm (Holdings) PLC ("TC BioPharm" or the "Company") (NASDAQ: TCBP) a clinical stage biotechnology company developing platform allogeneic gamma-delta T cell therapies for cancer, reported that it has selected of Fortrea (FTRE) as the Company’s Contract Research Organization (CRO) for global trials, including ACHIEVE and ACHIEVE2 (Press release, TC Biopharm, NOV 2, 2023, View Source [SID1234636827]).

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The trials, in the UK and US respectively, will be managed by Fortrea on an ongoing basis, creating a vertically integrated clinical trial program which allows for increased operational efficiencies, resulting in better data management and review as well as value creation. TC BioPharm expects to generate cash savings through the creation of these efficiencies by consolidating CRO services under a single entity.

"Fortrea is a leading global CRO who we believe brings a wealth of knowledge and experience that is expected to increase the likelihood of success in both ACHIEVE and ACHIEVE2," said CEO Bryan Kobel. "By consolidating these trials under a single CRO we have established a unified database for the trial management, removed potential miscommunication issues, and eliminated an onerous cost structure, which we believe will create cost savings. We appreciate Fortrea taking on these exciting trials with us and look forward to data read outs in 2024."

On November 2, 2023 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancer, chronic hepatitis B (CHB), and age-related diseases, reported that results from three clinical studies of lisaftoclax (APG-2575), a key candidate drug in the Company’s pipeline, have been selected for presentations at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, marking the second consecutive year in which clinical results of lisaftoclax were selected (Press release, Ascentage Pharma, NOV 2, 2023, View Source;ascentage-pharma-to-present-results-from-three-clinical-studies-of-bcl-2-inhibitor-lisaftoclax-apg-2575-including-the-first-data-in-aml-and-mm-301976616.html [SID1234636826]). This year, results from multiple clinical studies on two of Ascentage Pharma’s lead drug candidates (olverembatinib and lisaftoclax) have been selected for presentations at the ASH (Free ASH Whitepaper) Annual Meeting.

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Developed by Ascentage Pharma, lisaftoclax is an orally available Bcl-2 inhibitor with a wide therapeutic window in multiple hematologic malignancies and solid tumors. The investigational clinical data of lisaftoclax in patients with chronic lymphocytic leukemia (CLL), to be presented at the ASH (Free ASH Whitepaper) Annual Meeting this year, once again demonstrate the drug’s efficacy and favorable tolerability in patients with CLL who were heavily pretreated and had prior exposure to BTK inhibitors. In two other abstracts on lisaftoclax, results were disclosed from clinical studies of the drug as a single agent and in combination regimens in multiple hematologic malignancies, including relapsed/refractory (R/R) multiple myeloma (MM) and acute myeloid leukemia (AML).

The ASH (Free ASH Whitepaper) Annual Meeting is one of the largest gatherings of the international hematology community, bringing together the latest and most cutting-edge scientific research in the pathogenesis and clinical treatment of hematologic diseases. The 65th ASH (Free ASH Whitepaper) Annual Meeting will take place on December 9-12, 2023, both online and in-person, in San Diego, CA (United States).

"Lisaftoclax is the first Bcl-2 inhibitor in China and the second globally that has demonstrated promising efficacy. Clinical results to be presented at the ASH (Free ASH Whitepaper) Annual Meeting this year further validate the drug’s potential as an alternative treatment option for a number of hematologic malignancies, including R/R CLL," said Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma. "In addition, we will also present data of a few more clinical studies that will underscore our broad progress in new drug discovery and clinical development. Moving forward, we will continue to expeditiously advance our clinical development programs globally for the benefit of patients in China and around the world."

Studies of Ascentage Pharma’s Drug Candidates to be presented at ASH (Free ASH Whitepaper) 2023.

Drug Candidate

Title

PI/Presenter

Institution

Abstract#

Format

Olverembatinib

（HQP1351）

Olverembatinib (HQP1351) Demonstrates Efficacy Vs. Best Available Therapy (BAT) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant Chronic Myeloid Leukemia Chronic-Phase (CML-CP) in a Registrational Randomized Phase 2 Study

Qian Jiang

Xiaojun Huang

The Peking University People’s Hospital

#869

Oral Report

Olverembatinib Combined with Venetoclax and Reduced-Intensity Chemotherapy for Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Early results from a phase II study

Xiaoyuan Gong

Institute of Hematology and Blood Diseases Hospital, the Chinese Academy of Medical Sciences

#827

Oral Report

Update of Olverembatinib (HQP1351) Overcoming Ponatinib and/or Asciminib Resistance in Patients (Pts) with Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)

Elias Jabbour

Hagop Kantarjian

MD Anderson Cancer Center

#1798

Poster

Presentation

Combination of Liposome Mitoxantrone, Venetoclax, Homoharringtonine, and Olverembatinib (HQP1351) (MVHO) in Pediatric Patients with Refractory or Recurrent Acute Myeloid Leukemia (AML): Case Series

Wenting Hu

Shuhong Shen

Department of Hematology & Oncology, Shanghai Children’s Medical Center of Shanghai Jiao Tong University School of Medicine

#2840

Poster

Presentation

Combination of Olverembatinib and VP Regimen As First-Line Therapy for Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Gaixiang Xu

Jie Jin

The First Affiliated Hospital, Zhejiang University School of Medicine

#4205

Poster

Presentation

Olverembatinib(HQP1351)-Based Therapy in Adults with Relapsed or Refractory Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Advanced Chronic Myeloid Leukemia: Results of the Real-Life Study

Na Xu

Nanfang Hospital of Southern Medical University

#4538

Poster

Presentation

Frontline Combination of 3 Generation TKI Olverembatinib and Blinatumomab for Ph+/Phlike ALL Patients

Hongsheng Zhou

Nanfang Hospital of Southern Medical University

#1504

Poster

Presentation

Lisaftoclax

APG-2575

Updated Efficacy and Safety Results of Lisaftoclax (APG-2575) in Patients (pts) with Heavily Pretreated Chronic Lymphocytic Leukemia (CLL): Pool Analysis of Two Clinical Trials

Keshu Zhou

Jianyong Li

Jianxiang Wang

Henan Cancer Hospital,

Jiangsu Province Hospital

Institute of Hematology and Blood Diseases Hospital, the Chinese Academy of Medical Sciences

#1900

Poster

Presentation

Safety and Efficacy of Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor (BCL-2i), in Relapsed or Refractory (R/R) or Treatment-Naïve (TN) Patients (Pts) with Acute Myeloid leukemia (AML), Myelodysplastic Syndrome (MDS), or Other Myeloid Neoplasms

Huafeng Wang

Jie Jin

The First Affiliated Hospital, Zhejiang University School of Medicine

#2925

Poster

Presentation

First Report on the Effects of Lisaftoclax (APG-2575） in Combination with Novel Therapeutic Regimens in Patients with Relapsed or Refractory Multiple Myeloma (R/R MM） or Immunoglobulin Light-Chain (Amyloid Light-Chain [AL]） Amyloidosis

Sikander Ailawadhi

Asher A. Chanan-Khan

Mayo Clinic

#2016

Poster

Presentation

The abstracts of lisaftoclax presented at the 2023 ASH (Free ASH Whitepaper) Annual Meeting are as follows (for details on the abstracts featuring olverembatinib, please refer to a separate press release published at the same time):

Updated Efficacy and Safety Results of Lisaftoclax (APG-2575) in Patients (pts) with Heavily Pretreated Chronic Lymphocytic Leukemia (CLL): Pool Analysis of Two Clinical Trials

Format: Poster Presentation
Abstract: #1900
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster I
Time: Saturday, December 9, 2023, 5:30 PM – 7:30 PM (Pacific Time) / Sunday, December 10, 2023, 9:30 AM – 11:30 AM (Beijing Time)

Highlights:

This abstract reported updated data from long-term follow-ups in two Phase 1b/2 studies of lisaftoclax (APG-2575-CN001 [NCT03913949] and APG-2575-CC101 [NCT04494503]) in patients with CLL.

In the 2 studies, lisaftoclax was administered orally once daily in 28-day cycles, in 100 mg, 200 mg, 400 mg, 600 mg, and 800 mg dose cohorts. Under close monitoring for prevention and early detection of tumor lysis syndrome (TLS), patients were treated (with a daily dose ramp-up schedule) until disease progression, intolerable toxicity, death, or any other reason for termination.

As of April 27, 2023, a total of 47 patients with CLL were enrolled. The median (range) duration of follow-up was 14.06 (0.70-30.2) months. The median (range) age was 58 (34-80) years. At enrolment, 53.2% of patients were in Rai stage III/IV, and 48.9% of patients were in Binet stage C. 44.7% of patients had received ≥3 lines of treatment; 66.0% of patients had received ≥2 lines of treatment; 23.4% of patients were treated with Bruton tyrosine kinase inhibitors (BTKis); and 55.3% were treated with a CD20 monoclonal antibody. 68.1% (32) of patients discontinued the study due to disease progression (51.1%), consent withdrawal (6.4%), adverse events (AEs) (2.1%), investigator’s decision (2.1%), poor compliance (2.1%), protocol deviation (2.1%), and other reasons (2.1%).

The overall response rate (ORR) in patients with CLL was 73.3% (33/45), and the complete response (CR)/incomplete hematological recovery (Cri) rate was 24.4% (11/45).

In total, 76.6% (36) of patients experienced grade ≥3 treatment-emergent adverse events (TEAEs); 27.7% (13) experienced serious AEs (SAEs). Treatment-related adverse events (TRAEs) were observed in 95.7% (45) of patients, of whom 68.1% (32) experienced grade ≥3 TRAEs and 14.9% (7) experienced SAEs. One incident of TLS was reported.

Conclusions: Lisaftoclax demonstrated significant efficacy and favorable tolerability in patients with CLL who were heavily pretreated and had prior exposure to BTKis.
Safety and Efficacy of Lisaftoclax (APG-2575), a Novel BCL-2 Inhibitor (BCL-2i), in Relapsed or Refractory (R/R) or Treatment-Naïve (TN) Patients (Pts) with Acute Myeloid leukemia (AML), Myelodysplastic Syndrome (MDS), or Other Myeloid Neoplasms

Format: Poster Presentation
Abstract: #2925
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Time: December 10, 2023, Sunday, 6:00 PM – 8:00 PM (Pacific Time) / December 11, 2023, Monday, 10:00 AM – 12:00 PM (Beijing Time)

Highlights:

This multicenter, open-label, Phase 1 study in China evaluated the efficacy and safety of lisaftoclax alone or combined with azacitidine (AZA) or homoharringtonine (HHT) in patients with treatment-naïve or R/R AML, MDS, or other myeloid neoplasms.

Trial design:
In part one, lisaftoclax as a single agent was orally administered once daily at 200, 400, 600, or 800 mg, using a "3+3" dose escalation design. In part two, patients with R/R AML, mixed-phenotype acute leukemia (MPAL), blastic plasmacytoid dendritic cell neoplasm (BPDCN), or chronic myelomonocytic leukemia (CMML) were enrolled in Cohorts A, B, and C; while patients with higher-risk MDS were enrolled in Cohort D; and older or chemotherapy-ineligible (unfit) patients with treatment-naïve AML were enrolled in Cohort E. Lisaftoclax was administered orally once daily in 28-day cycles (or 14-day cycles for patients with MDS). A daily ramp-up schedule was adopted to prevent TLS. Cohort A was treated with lisaftoclax combined with low-dose HHT (1 mg daily on days [d] 1-14); Cohort B was treated with lisaftoclax combined with standard-dose HHT (2 mg/m2 daily on d1-7); Cohort C, D, E were treated with lisaftoclax combined with AZA (75 mg/m2 daily on d1-7). Dose-limiting toxicity (DLT) was assessed during the first cycle.

As of July 19, 2023, a total of 115 patients were enrolled, including 89 patients with AML (64 R/R; 25 TN older/unfit), 22 with MDS (7 R/R MDS; 15 TN MDS), 2 MPAL, 1 CMML, and 1 BPDCN. A total of 13 patients received lisaftoclax monotherapy and 102 patients received combination regimens.

Efficacy results: In patients treated with lisaftoclax monotherapy, the ORR and composite remission rate (CRc=complete remission [CR] + CR with incomplete blood count recovery [CRi]) were each 8.3% (1/12). Lisaftoclax at 600 mg and 800 mg were chosen as exploratory doses for combination therapies. Among the 21 efficacy evaluable patients with TN AML in Cohort E, the ORR and CRc were 71.4% and 47.6%, respectively. Among the 36 efficacy evaluable patients with R/R AML or myeloid neoplasm in Cohort C, the ORR and CRc were 75.0% and 44.4%, respectively. The progression-free survival (PFS) was 10.22 months. Among patients in Cohort B, the ORR and CRc were both 75.0%. Among patients in Cohort D, the ORR was 70.0%, the CR/marrow CR rate was 60.0%。

Safety results: Common TEAEs included hematologic toxicity, electrolyte imbalances, and diarrhea. No TLS was reported during the study and dose-limiting toxicities (DLTs; pneumonia, respiratory failure, and heart failure) were observed in 1 patient in Cohort C. 13 patients who received lisaftoclax monotherapy experienced TEAEs and grade ≥3 TEAEs, and 4 (30.8%) patients experienced SAEs. In patients treated with lisaftoclax combined with HHT, 12 (85.7%) experienced TEAEs and grade ≥3 TEAEs, and 2 (14.3%) experienced SAEs. In the 75 patients treated with lisaftoclax combined with AZA, 100% of patients experienced TEAEs, including 55 (73.3%) who experienced grade ≥3 TEAEs and 18 (24.0%) SAEs.

Increased systemic exposure of lisaftoclax was discerned as the dosage escalated from 200 mg to 800 mg. Compared to lisaftoclax monotherapy, no significant difference was observed in the pharmacokinetic profile of lisaftoclax combined with AZA or HHT.

Conclusions: Lisaftoclax, in monotherapy or combination regimens, showed encouraging efficacy and favorable tolerability profiles in patients with R/R AML or MDS and older/unfit patients with TN AML.
First Report on the Effects of Lisaftoclax (APG-2575） in Combination with Novel Therapeutic Regimens in Patients with Relapsed or Refractory Multiple Myeloma (R/R MM） or Immunoglobulin Light-Chain (Amyloid Light-Chain [AL]） Amyloidosis

Format: Poster Presentation
Abstract: #2016
Session: 653. Multiple Myeloma: Prospective Therapeutic Trials: Poster I
Time: December 9, 2023, Saturday, 5:30 PM – 7:30 PM (Pacific Time) / December 10, 2023, Sunday, 9:30 AM – 11:30 AM (Beijing Time)

Highlights:

This multicenter study was designed to evaluate the safety and efficacy of lisaftoclax combination regimens in patients with R/R MM or R/R AL amyloidosis.
This study has three treatment arms that included Arm A: lisaftoclax combined with pomalidomide and dexamethasone in patients with R/R MM; Arm B: lisaftoclax combined with daratumumab, lenalidomide, and dexamethasone in patients with R/R MM; and Arm C: lisaftoclax combined with pomalidomide and dexamethasone in patients with R/R amyloidosis. Lisaftoclax was administered orally once daily (QD) at 5 dose levels (400 mg, 600 mg, 800 mg, 1,000 mg, and 1,200 mg) without ramp-up in 28-day cycles. Pomalidomide, daratumumab, and lenalidomide were administered per label use. Dexamethasone 40 mg (20 mg for patients aged >75 years) was administered on Days 1, 8, 15, and 22 of 28-day cycles.
As of July 3, 2023, a total of 30 patients were enrolled. Among them, 22, 3, and 5 patients were enrolled into Arms A, B, and C, respectively. 66.7% of patients were male and the median (range) age was 70.5 (24-88) years. All patients were previously exposed to multiple lines of treatment, with a median (range) line of prior therapies of 4 (1-19). 18 patients were triple-class-exposed, including 7 who had received pomalidomide and 3 who harbored the t(11;14) chromosomal abnormality.
Safety results: A total of 19 patients experienced lisaftoclax treatment related AEs, including nausea (16.7%), neutropenia (16.7%); thrombocytopenia, leukopenia, abdominal distension, constipation, or diarrhea (6.7% each). A total of 7 patients experienced grade ≥3 TRAEs, including neutropenia (10.0%), febrile neutropenia (3.3%), iron deficiency anemia (3.3%), thrombocytopenia (3.3%), prolonged electrocardiogram QT interval (3.3%), and acute kidney injury (3.3%). Two patients experienced lisaftoclax-related SAEs, including 1 acute kidney injury and 1 febrile neutropenia.
Efficacy results: In Arm A, 21 patients with R/R MM were efficacy evaluable, with an ORR (partial response [PR] + very good partial response [VGPR]) of 66.7%. In Arm B, 1 patient with R/R MM achieved PR and another achieved VGPR. In Arm C, 3 patients with R/R amyloidosis achieved a hematologic VGPR. The ORR was 60% and 1 patient experience organ function improvement.
Conclusions: Lisaftoclax combination regimens were well tolerated and demonstrated potent antitumor activity in patients with R/R MM and R/R amyloidosis.
* Lisaftoclax (APG-2575) is an investigational drug that has not been approved in any country and region.