The primary goal of this study is to establish the safety of chronic Convection Enhanced Delivery (CED) of the chemotherapeutic drug Topotecan for patients with recurrent malignant glioma that harbors the Isocitrate Dehydrogenase mutation (IDH-mut). The secondary goal of the study is to study drug distribution and assess the tumor response to prolonged continuous CED of Topotecan.
Convection Enhanced Delivery is a novel method of drug delivery that allows administration of a drug directly to the brain. In CED, a drug pump is placed under the skin in the chest or abdominal region. The pump is connected to a catheter that is tunneled underneath the skin to the brain. The tip of the catheter then infuses Topotecan directly onto the brain tumor. There will be a total of four treatment infusions over the course of 23-29 days, with a 5-7-day rest period between each infusion. Throughout this period, patients' health will be monitored through imaging, blood draws, and regular exams. At the end of the treatment period, the pump will be removed, followed by resection of the tumor. Patients will be followed for the duration of their lives.
This is the investigator's second clinical trial studying CED of TPT in recurrent glioma. In the prior Phase 1b trial, chronic pulsatile CED safely and effectively delivered Topotecan to patients with IDH mutant recurrent Glioblastoma (WHO grade 4).

Start Date04 Oct 2025

Sponsor / Collaborator

Columbia University

NCT06801834

/ Not yet recruitingPhase 3

A Global, Multicenter, Randomized, Open-label, Phase 3 Study of Sacituzumab Govitecan Versus Standard of Care (SOC) in Participants With Previously Treated Extensive Stage Small Cell Lung Cancer (ES-SCLC)

The goal of this clinical study is to learn more about the study drug sacituzumab govitecan (SG; Trodelvy®; GS-0132; IMMU 132), versus standard of care (SOC) in participants with previously treated extensive stage small cell lung cancer (ES-SCLC).
The primary objectives of this study are to compare the effect of SG to SOC on objective response rate (ORR) as assessed by blinded independent central review (BICR) according to the Response Evaluation Criteria in Solid Tumors and to compare the effect of SG to SOC on overall survival (OS).

Start Date01 Apr 2025

Sponsor / Collaborator

Gilead Sciences, Inc.

NCT06647953

/ Not yet recruitingPhase 3IIT

Prospective Treatment of Types I, II and III Pleuropulmonary Blastoma (PPB)

This phase III trial tests how well surgery plus chemotherapy compared to surgery alone works in treating patients with type I pleuropulmonary blastoma (PPB), and tests how well surgery plus standard chemotherapy with the addition of topotecan works compared to surgery plus standard chemotherapy alone in treating patients with type II and III PPB.
Historically, most children with type I PPB had surgery and approximately 40% of children with type I PPB received chemotherapy following their surgery, usually for 22-42 weeks. There has not been a consistent standard for which children with type I PPB receive chemotherapy after surgery. For patients whose tumor has been removed completely with surgery, observation without chemotherapy may work as well as giving chemotherapy after surgery in preventing a return of the PPB tumor.
The standard chemotherapy for patients with types II or III PPB in the United States is four cycles of IVADo (ifosfamide, vincristine, dactinomycin, and doxorubicin) followed by 8 cycles of IVA (ifosfamide, vincristine and dactinomycin). Ifosfamide is in a class of medications called alkylating agents. It works by slowing or stopping the growth of tumor cells in the body. Vincristine is in a class of medications called vinca alkaloids. It works by stopping tumor cells from growing and dividing and may kill them. Dactinomycin is a type of antibiotic that is only used in cancer chemotherapy (antineoplastic antibiotic). It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill tumor cells. Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill tumor cells. It also blocks a certain enzyme needed for cell division and DNA repair. Topotecan is in a class of medications called topoisomerase I inhibitors. It works by interfering with tumor cell DNA which kills them. Giving topotecan in addition to standard IVADo and IVA chemotherapy regimens may shrink the cancer as well as or better than the standard therapy or could decrease the chance the tumor spreads while causing fewer side effects.

Start Date17 Mar 2025

Sponsor / Collaborator

The Children's Oncology Group Foundation, Inc.

100 Clinical Results associated with Topotecan Hydrochloride

100 Translational Medicine associated with Topotecan Hydrochloride

100 Patents (Medical) associated with Topotecan Hydrochloride

5,408

Literatures (Medical) associated with Topotecan Hydrochloride

03 May 2025·Journal of biomolecular structure & dynamics

Synergy between human DNA ligase I and topoisomerase 1 unveils new therapeutic strategy for the management of colorectal cancer

Article

Author: Maurya, Pooja ; Sashidhara, Koneni V. ; Gupta, Sampa ; Rawat, Rohit Singh ; Krishna, Shagun ; Siddiqi, Mohammad Imran ; Banerjee, Dibyendu

DNA topoisomerase 1 (Topo 1) is a pivotal player in various DNA processes, including replication, repair, and transcription. It serves as a target for anticancer drugs like camptothecin and its derivatives (Topotecan and SN-38/Irinotecan). However, the emergence of drug resistance and the associated adverse effects, such as alopecia, anemia, dyspnea, fever, chills, and painful or difficult urination, pose significant challenges in Topo 1-targeted therapy, necessitating urgent attention. Human DNA Ligase 1 (hLig I), recognized primarily for its role in DNA replication and repair of DNA breaks, intriguingly exhibits a DNA relaxation activity akin to Topo 1. This raised the hypothesis that hLig I might compensate for Topo 1 inhibition, contributing to resistance against Topo 1 inhibitors. To explore this hypothesis, we assessed the efficacy of hLig I inhibition alone and in combination with Topo 1 in cancer cells. As anticipated, the overexpression of hLig I was observed after Topo 1 inhibition in colorectal cancer cells, affirming our hypothesis. Previously identified as an inhibitor of hLig I's DNA relaxation activity, compound 27 (C 27), when combined with Topotecan, demonstrated a synergistic antiproliferative effect on colorectal cancer cells. Notably, cells with downregulated hLig I (via siRNA, inhibitors, or genetic manipulation) exhibited significantly heightened sensitivity to Topotecan. This observation strongly supports the concept that hLig I contribute to resistance against clinically relevant Topo 1 inhibitors in colorectal cancers. In conclusion, our findings offer evidence for the synergistic impact of combining hLig I inhibitors with Topotecan in the treatment of colorectal cancers, providing a promising strategy to overcome resistance to Topo 1 inhibitors.Communicated by Ramaswamy H. Sarma.

01 Mar 2025·ENVIRONMENTAL TOXICOLOGY

Revolutionizing prognosis: Introducing cell death index (CDI) as a powerful prognostic tool for CSCC patients

Article

Author: Lou, Jun ; Zhang, Ke ; Yu, Qingqing ; Tang, Rongjun ; Li, Lingdi ; Yao, Qing

Abstract:

Background:

Cervical squamous cell carcinoma (CSCC) threatens the body health of women worldwide. This study aimed to foster a new concept of prognostic indicator named cell death index (CDI).

Methods:

RNA‐seq and scRNA‐seq datasets were downloaded from the GEO and TCGA database as the training and validation cohorts. Programmed cell death (PCD)‐related gene signatures were obtained from published research. The construction of prognostic model was performed based on CDI value. Patients with CSCC were divided into high‐ and low‐CDI groups. We explored the differences in overall survival time, immune infiltration, mutation status, and drug sensitivity between high and low CDI groups by R software.

Results:

We constructed prognostic model to calculate the CDI value with 23 genes. Patients with high CDI have shorter survival time than those with low CDI. CDI was considered a risk factor compared to other characteristics. The nomogram model estimated overall survival (OS) at 1, 3, and 6 years, with age, Stage, and CDI, indicating the accuracy of the model in predicting 1‐, 3‐, and 6‐year survival rates. CDI values were negatively correlated with most immune checkpoint genes. We measured the significant drug sensitivity of Mitoxantrone, Sabutoclax, Sepantronium bromide, Topotecan, BI‐2536, and BMS‐754807 between high‐ and low‐CDI groups with significant correlation.

Conclusion:

This investigation constructed a novel effective prognostic indicator of CDI in patients with CSCC and identified potential genes associated with cell death that could be targeted for prognosis and treatment of CSCC.

01 Feb 2025·EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Structure-activity relationship study of novel evodiamine amino acid conjugates with potent anti-colorectal cancer efficacy

Article

Author: Hu, Zecheng ; Jiang, Weifan ; Wang, Zhen ; Peng, Xue ; Zhuo, Linsheng ; Xiong, Yongxia ; An, Zhigang ; Zhang, Siyi ; Lei, Zhengwen ; Chen, Shuting ; Wei, Xiuzhen ; Mo, Hanxuan ; Wu, Junbo ; Zhang, Xi ; Peng, Ying

Evodiamine has been a promising lead structure with broad-spectrum antitumor activity. Druggability optimization is the most challenging part of evodiamine-based lead-to-candidate campaign. Amino acids as building blocks for conjugates are widely incorporated into approved drug and drug candidates, demonstrating highly attractive druggability. Herein, a series of evodiamine amino acid conjugates were designed and synthesized based on the evodiamine lead compound (±)-8b discovered in our previous work. The structure-activity relationship (SAR) studies culminated in the identification of a promising conjugate (-)-15h featuring a N-Boc-l-glutamine group and a chiral carbon atom (sinister), which exhibited nanomolar antiproliferative activity against LoVo and RKO colorectal cancer cells. Moreover, (-)-15h could inhibit topoisomerases I, arrest the cell cycle in the G2/M phase, and induce apoptosis. Importantly, (-)-15h (tumor growth inhibition rate was 82.53 % in 40 mpk) showed better efficacy and tolerability to that of parent compound (-)-8b (tumor growth inhibition rate was 51.22 % in 40 mpk) in LoVo xenograft model. Further, (-)-15h (tumor growth inhibition rate was 70.09 % in 40 mpk) showed comparable efficacy and better tolerability to that of topotecan (tumor growth inhibition rate was 70.67 % in 0.5 mpk) in HT-29 xenograft model. Collectively, this study further provided a strong scientific basis for amino acid-based structural modifications and a drug lead for anti-colorectal cancer applications.

157

News (Medical) associated with Topotecan Hydrochloride

22 Feb 2025

·synapse.patsnap.com

AOH1996: The Ultimate Weapon to Annihilate All Solid Tumours

Proliferating Cell Nuclear Antigen (PCNA) is a protein present in all eukaryotic cells that plays a crucial role in DNA synthesis and repair. It is widely used as a biomarker for tumor progression and is also considered a potential target for cancer therapy. Small molecule targeting of transcription-replication conflict for selective chemotherapy"Holy grail" moleculeRecently, a team from City of Hope in California, United States, published a study showing that a new type of anticancer drug targeting PCNA can eliminate all solid tumors. This drug, called AOH1996, hailed as ‘holy grail’ molecule by many, has been shown to be effective in preclinical studies of breast cancer, prostate cancer, brain cancer, ovarian cancer, cervical cancer, skin cancer, and lung cancer cells. The study, titled "Small molecule targeting of transcription-replication conflict for selective chemotherapy," was published in the Cell Chemical Biology journal. The new potential anti-cancer drug that targets genomic instability in cancer cells shows promise as an oral treatment option with few side effects. Cancer cells are known to have elevated levels of DNA damage and suffer from defects in DNA repair mechanisms, resulting in genomic instability. This instability creates an opportunity for drugs to selectively target cancer cells. In their study, the researchers honed in on transcription-replication conflicts, a significant source of genomic instability in cancer, as the key focus of their investigation. They targeted PCNA through medicinal chemistry approaches and showed that AOH1996 binds to PCNA and inhibits its interaction with RNA polymerase II, a key protein involved in transcription. AOH1160 analog interactions with PCNAWhen tested in cancer cell lines, AOH1996 selectively killed cancer cells while having little effect on normal cells. It induced DNA double-strand breaks, cell cycle arrest and apoptosis in cancer cells. It also sensitized cancer cells to other anti-cancer drugs like cisplatin and topotecan. In mouse models of human cancer, daily treatment with the drug AOH1996 considerably slowed tumor growth with no noticeable side effects. The highest dose that did not cause adverse effects was more than 6 times the effective dose in mice and dogs. Researchers intend to further examine the drug's distribution within the body, activity, and safety profile to ascertain its suitability for human testing. If clinical trials are positive, AOH1996 may present a novel option for some cancer patients by acting on a molecular defect while possibly resulting in fewer side effects compared to current treatments. The drug selectively attacked the cancer cells, leaving normal cells unharmed. Clinical trials underwayLead author Linda Malkas, a professor in the Molecular Diagnostic and Experimental Therapeutics Department at City of Hope, said the results of the cell and animal models were encouraging, and Phase I clinical trials are currently underway. "AOH1996 can inhibit tumor growth as a monotherapy or combination therapy in cell and animal models without causing toxicity," she said. Interaction of AOH1996 with PCNALong Gu, the study's main author, said that no one had previously considered PCNA as a therapeutic target because it was considered "undruggable." According to a statement from City of Hope, the first patient treated with AOH1996 is in good condition. Phase I clinical trials are being conducted at City of Hope in Los Angeles to determine the maximum tolerated dose of the drug and evaluate its preliminary efficacy. During DNA replication, replication stress caused by extracellular and intracellular factors can lead to replication fork stalling or termination. If cells cannot respond appropriately to this risk, chromosomal breaks and rearrangements can occur, leading to genomic instability. AOH1996 was named after Anna Olivia Healy, who was born in 1996 and was diagnosed with a rare childhood cancer, neuroblastoma, at the age of nine. She passed away later on. Linda Malkas, the head of the team, has been working on the development and research of anticancer drugs for the past 20 years. The team used computer modeling to simulate molecular interactions with the L126-Y133 region of PCNA. The model simulated molecular interactions of key proteins involved in DNA replication. After multiple simulations and analysis, the team discovered AOH1996, which showed potential to inhibit PCNA activity, thereby disrupting DNA replication in cancer cells and inducing cell death. The effect of AOH1996 is mediated through PCNA interaction with RPB1In their experiments, the researchers tested AOH1996 on more than 70 cancer cell lines and several normal control cells. They discovered that AOH1996 specifically targets cancer cells by disrupting the normal cell cycle. What's even more intriguing is that the study found that AOH1996 increases the vulnerability of cancer cells to chemical agents that cause DNA or chromosome damage, such as the chemotherapy drug cisplatin. This implies that AOH1996 could be an effective tool for combination therapy and the development of new chemotherapy drugs. As of now, the exclusive license for AOH1996 has been granted to RLL, LLC by City of Hope, a biotechnology company co-founded by Malkas. Reference Gu et al., Small molecule targeting of transcription-replication conflict for selective chemotherapy, Cell Chemical Biology (2023). The content above comes from the network. if any infringement, please contact us to modify.

15 Jan 2025

·ir.zailaboratory.com

Zai Lab Announces Positive Topline Results for TIVDAK in the China Subpopulation of the Global Phase 3 innovaTV 301 Trial in Patients with Recurrent or Metastatic Cervical Cancer

Improved overall survival (OS), progression-free survival (PFS) and confirmed objective response rate (ORR) were observed in the China subpopulation treated with TIVDAK compared to chemotherapy, consistent with those in the global population The safety profile of TIVDAK among the China subpopulation was manageable and consistent with that observed in the global population Zai Lab intends to submit a New Drug Application (NDA) to China’s National Medical Products Administration (NMPA) in the first quarter of 2025 Zai Lab will leverage its commercial footprint of ZEJULA in women’s cancer to bring the medicine to patients in China if approved SHANGHAI & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Jan. 15, 2025-- Zai Lab Limited (NASDAQ: ZLAB; HKEX: 9688) today announced positive topline results from the China subpopulation of the global Phase 3 innovaTV 301 study, demonstrating a clinically meaningful improvement in overall survival with TIVDAK treatment for patients with previously treated recurrent or metastatic cervical cancer compared to chemotherapy. The China subpopulation results were consistent with those in the global population: TIVDAK demonstrated a 45% reduction in the risk of death compared to chemotherapy (HR: 0.55 [95% CI: 0.27-1.15] in the China subpopulation who had received prior standard systemic therapies, with more than half of this Chinese population having received prior anti-PD(L)1 therapy. Median OS for patients treated with TIVDAK was not reached versus chemotherapy 10.7 months [95% CI: 6.0-not reached] with a median follow-up of 11.5 months. Secondary endpoints of PFS and confirmed ORR also favored treatment with TIVDAK compared to chemotherapy. The safety profile of TIVDAK in the China subpopulation was manageable and consistent with the global profile. “Recurrent or metastatic cervical cancer remains a significant challenge for patients, highlighting a critical unmet need for effective treatments that extend survival after relapse,” said Dr. Rafael Amado, M.D., President, Head of Global Research and Development at Zai Lab. “The consistent and positive results in the China subpopulation of the global Phase 3 study reinforce the potential for TIVDAK, the only ADC therapy in this disease setting, to increase options in this therapeutically unmet clinical setting. If approved, we expect TIVDAK to add to ZEJULA and augment our commercial franchise in women’s tumors.” “There are approximately 150,000 new cases of cervical cancer annually in China1, and patients face limited treatment options once their cancer recurs or spreads after initial treatment,” said Dr. Lingying Wu, Professor of the Department of Gynecologic Oncology of National Cancer Center / Cancer Hospital Chinese Academy of Medical Sciences. “While the recent adoption of immunotherapy as a first-line treatment in China represents progress, there is a lack of effective options for patients following relapse. The promising results from TIVDAK, which demonstrated superior survival extension in patients whose disease progressed after initial treatments, including prior anti-PD(L)1 treatment, offer hope for addressing this critical unmet need.” In April 2024, the U.S. Food and Drug Administration (FDA) approved the supplemental Biologics License Application (sBLA) granting full approval for TIVDAK® (tisotumab vedotin-tftv) for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. The approval was based on results from the global, randomized, Phase 3 innovaTV 301 clinical trial (NCT04697628), which met its primary endpoint, demonstrating overall survival (OS) benefit in adult patients with previously treated recurrent or metastatic cervical cancer treated with TIVDAK compared to chemotherapy. TIVDAK demonstrated a 30% reduction in the risk of death compared to chemotherapy (hazard ratio [HR]: 0.70 [95% CI: 0.54-0.89], two-sided p=0.0038)2. Median OS for patients treated with TIVDAK was 11.5 months [95% CI: 9.8-14.9] versus chemotherapy 9.5 months [95% CI: 7.9-10.7]. PFS and confirmed ORR were also significantly improved compared to chemotherapy. The safety profile of TIVDAK was consistent with its known safety profile as presented in the U.S. prescribing information, and no new safety signals were observed. Based on these encouraging results, Zai Lab intends to submit an NDA for TIVDAK to China’s National Medical Products Administration (NMPA) in the first quarter of 2025. The full China subpopulation data will be presented at a future medical conference in 2025. About innovaTV 301 Trial Design The innovaTV 301 trial (NCT04697628) is a global, 1:1 randomized, open-label Phase 3 trial evaluating TIVDAK® (tisotumab vedotin) versus investigator’s choice of single agent chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) with recurrent or metastatic cervical cancer who received chemotherapy. Patients with recurrent or metastatic cervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology, and disease progression during or after treatment with chemotherapy doublet +/- bevacizumab and an anti-PD-(L)1 agent (if eligible) are included. The primary endpoint was overall survival. The main secondary outcomes were progression-free survival and objective response rate. The study was conducted by Seagen, which was acquired by Pfizer in December 2023, in collaboration with Genmab, European Network of Gynaecological Oncological Trial Groups (ENGOT, study number ENGOT cx-12) and the Gynecologic Oncology Group (GOG) Foundation (study number GOG 3057), as well as other global gynecological oncology cooperative groups. For more information about the Phase 3 innovaTV 301 clinical trial and other clinical trials with tisotumab vedotin, please visit www.clinicaltrials.gov. About Cervical Cancer in China Cervical cancer remains one of the leading causes of cancer death in women in China and globally. An estimated 150,000 new cases of cervical cancer occur annually in China1. Current treatment options are limited for patients with recurrent or metastatic cervical cancer with disease progression on or after systemic therapy. TIVDAK is well positioned to provide a new option for previously treated advanced cervical cancer patients who currently have limited treatment options and poor outcomes. About TIVDAK® (tisotumab vedotin) TIVDAK® (tisotumab vedotin) is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Pfizer’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Nonclinical data suggest that the anticancer activity of tisotumab vedotin is due to the binding of the ADC to TF-expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, tisotumab vedotin also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity. TIVDAK received accelerated approval from the FDA in September 2021 and full approval in April 2024 for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Please see full prescribing information, including BOXED WARNING for TIVDAK here. Zai Lab has an exclusive license from Seagen Inc., a company later acquired by Pfizer, to develop and commercialize TIVDAK in Greater China (mainland China, Hong Kong, Macau, and Taiwan, collectively). About Zai Lab Zai Lab (NASDAQ: ZLAB; HKEX: 9688) is an innovative, research-based, commercial-stage biopharmaceutical company based in China and the United States. We are focused on discovering, developing, and commercializing innovative products that address medical conditions with significant unmet needs in the areas of oncology, immunology, neuroscience and infectious disease. Our goal is to leverage our competencies and resources to positively impact human health worldwide. For additional information about Zai Lab, please visit www.zailaboratory.com or follow us at www.twitter.com/ZaiLab_Global. Zai Lab Forward-Looking Statements This press release contains forward-looking statements relating to our future expectations, plans, and prospects, including, without limitation, statements relating to our prospects and plans for developing and commercializing TIVDAK in Greater China, the potential benefits of TIVDAK, and the potential treatment of cervical cancer. These forward-looking statements may contain words such as “aim,” “anticipate,” “believe,” “could,” “estimate,” “expect,” “forecast,” “goal,” “intend,” “may,” “plan,” “possible,” “potential,” “will,” “would,” and other similar expressions. Such statements constitute forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements are not statements of historical fact or guarantees or assurances of future performance. Forward-looking statements are based on our expectations and assumptions as of the date of this press release and are subject to inherent uncertainties, risks, and changes in circumstances that may differ materially from those contemplated by the forward-looking statements. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including but not limited to (1) our ability to successfully commercialize and generate revenue from our approved products, (2) our ability to obtain funding for our operations and business decisions, (3) the results of our clinical and pre-clinical development of our product candidates, (4) the content and timing of decisions made by the relevant regulatory authorities regarding regulatory approvals of our product candidates, (5) risks related to doing business in China, and (6) other factors identified in our most recent annual and quarterly reports and in other reports we have filed with the U.S. Securities and Exchange Commission. We anticipate that subsequent events and developments will cause our expectations and assumptions to change, and we undertake no obligation to update or revise any forward-looking statements, whether as a result of new information, future events, or otherwise, except as may be required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date of this press release. Our SEC filings can be found on our website at www.zailaboratory.com and the SEC’s website at www.sec.gov. Notes: 1 Bingfeng Han et al., "Cancer incidence and mortality in China, 2022" Journal of the National Cancer Center, 2024. DOI: 10.1016/j.jncc.2024.01.006. 2 The threshold for statistical significance is 0.0226 (2-sided). View source version on businesswire.com: https://www.businesswire.com/news/home/20250115437262/en/ Investor Relations: Christine Chiou / Lina Zhang +1 (917) 886-6929 / +86 136 8257 6943 christine.chiou1@zailaboratory.com / lina.zhang@zailaboratory.com Media: Shaun Maccoun / Xiaoyu Chen +1 (857) 270-8854 / +86 185 0015 5011 shaun.maccoun@zailaboratory.com / xiaoyu.chen@zailaboratory.com Source: Zai Lab Limited

Phase 3Clinical ResultDrug ApprovalLicense out/inImmunotherapy

08 Jan 2025

·www.businesswire.com

Asher Bio Announces Clinical Trial Collaboration and Supply Agreement on Etakafusp Alfa (AB248) in Combination with Bispecific T-cell Engager in Patients with Small Cell Lung Cancer

SOUTH SAN FRANCISCO, Calif.--( BUSINESS WIRE )--Asher Biotherapeutics, a biotechnology company developing precisely-targeted immunotherapies for cancer and infectious diseases, today announced a clinical trial collaboration and supply agreement with Amgen (NASDAQ:AMGN) to evaluate etakafusp alfa (formerly known as AB248), Asher Bio’s investigational CD8+ T cell targeted interleukin-2 (IL-2) immunotherapy, in combination with IMDELLTRA ® (tarlatamab), Amgen’s DLL3-targeting Bispecific T-cell Engager (BiTE ® ) therapy, in patients with extensive-stage small cell lung cancer (ES-SCLC). “ This clinical trial collaboration and supply agreement with Amgen allows us to further expand on the Phase 1 results for etakafusp alfa in a new combination with IMDELLTRA ® in a global Phase 1b study in ES-SCLC,” said Don O’Sullivan, Ph.D., Chief Business Officer of Asher Bio. “ Based on emerging data to date, we believe etakafusp alfa has the potential to improve the efficacy of T cell engagers (TCEs) by selectively expanding the CD8+ T cell population, improving effector function, tumor infiltration and reversing TCE-induced T cell desensitization. We look forward to collaborating with Amgen to assess the potential for the novel combination to improve outcomes for patients with ES-SCLC.” As part of this collaboration agreement, Amgen will sponsor and operationalize a global Phase 1b study to evaluate the safety and early efficacy of etakafusp alfa in combination with IMDELLTRA ® in patients with ES-SCLC. Asher Bio will retain full ownership of etakafusp alfa and will supply Amgen with etakafusp alfa at no cost. About SCLC SCLC is one of the most aggressive and devastating solid tumor malignancies, with a median survival of approximately 12 months following initial therapy and a 3% five-year relative survival rate for ES-SCLC. 1,2,3 Current second-line treatments impart a short duration of response (median DoR: 3.3–5.3 months) and limited survival (median OS: 5.8-9.3 months), while current third-line treatments for SCLC, which consist primarily of chemotherapy, yield a short median DoR of 2.6 months and a median OS of 4.4-5.3 months. 4-8 SCLC comprises ~15% of the 2.4 million plus patients diagnosed with lung cancer worldwide each year. 9-11 Despite initial high response rates to first-line platinum-based chemotherapy, most patients quickly relapse within months and require subsequent treatment options. 13 About Etakafusp Alfa ( AB248) Etakafusp Alfa ( AB248 ) is a novel CD8+ T cell selective IL-2, generated by fusing a reduced potency IL-2 mutein to an anti-CD8β antibody. It was specifically engineered to selectively and potently activate CD8+ T-cells which are the immune cells that drive anti-tumor efficacy, while avoiding natural killer (NK) cells, which can act as a pharmacological sink and contribute to toxicity, and regulatory T (Treg) cells, which are immunosuppressive. Asher Bio is currently evaluating etakafusp alfa in a Phase 1a/1b clinical trial, AB248-101. The trial consists of a dose escalation and expansion phase to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of etakafusp alfa alone and in combination with pembrolizumab in subjects with locally advanced/metastatic solid tumors who failed prior therapies. Initial pharmacokinetic and pharmacodynamic data from the ongoing Phase 1a/1b clinical trial support etakafusp alfa’s proof of mechanism and activity with a highly differentiated clinical profile. Early data shows potent and selective CD8+ T cell activation without substantial changes to Treg and NK cell numbers and initial evidence of anti-tumor activity, including confirmed objective responses, with a generally well-tolerated safety profile. Please refer to www.clinicaltrials.gov (NCT05653882) for additional details related to this Phase 1a/1b clinical trial. About Asher Bio Asher Bio is a biotechnology company developing therapies to precisely engage specific immune cells to fight cancer and chronic viral infection. We utilize our proprietary cis-targeting platform to develop therapies engineered to overcome limitations of other immune-based treatments by selectively activating specific immune cell types with validated disease fighting functionality. Our candidates feature an antibody connected to a modified immunomodulatory protein, such as a cytokine. Our candidate design is intended to enable our candidates to selectively activate the desired immune cells and not other cells that contribute to toxicity or immune suppression. Our lead program etakafusp alfa (AB248), an IL-2 molecule specifically targeted to CD8+ effector T cells, is currently in Phase 1 trials for oncology. Our broader portfolio includes AB821, an IND-ready CD8-targeted IL-21 immunotherapy, and early-stage programs targeting CAR-T cells, myeloid cells and CD4+ T cells. Asher Bio was founded by Ivana Djuretic and Andy Yeung with support from Third Rock Ventures and is located in South San Francisco. For more information, please visit http://www.asherbio.com and follow us on X (formerly Twitter) @ AsherBio and on LinkedIn . 1 American Cancer Society. Lung Cancer Survival Rates. 2 Paz-Ares L, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open. 2022;7:100408. 3 Liu SV, Reck M, Mansfield AS, et al. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol. 2021;39:619-630. 4 Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. 5 Von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17(2):658-67. 6 Von Pawel J, Jotte R, Spigel DR, et al. Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer. J Clin Oncol. 2014;32(35):4012-9. 7 Coutinho AD, Shah M, Lunacsek OE, et al. Real-world treatment patterns and outcomes of patients with small cell lung cancer progression after 2 lines of therapy. Lung Cancer. 2019;127:53-58. 8 Borghaei H, Pundole X, Anderson E, et al. Treatment patterns and outcomes in recent US clinical practice for SCLC patients after two prior lines of therapy. Presentation at World Conference on Lung Cancer 2023. September 9-12, 2023; Singapore, SGP. Poster #EP13.07-03. 9 Oronsky B, Abrouk N, Caroen S, et al. A 2022 Update on Extensive Stage Small-Cell Lung Cancer (SCLC). J Cancer. 2022;13:2945-2953. 10 World Health Organization. Lung. 2020. 11 Sabari JK, Lok BH, Laird JH, et al. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol. 2017;14:549-561.

Phase 1ImmunotherapyPhase 3Phase 2

100 Deals associated with Topotecan Hydrochloride

External Link

KEGG	Wiki	ATC	Drug Bank
D02168	Topotecan Hydrochloride	L01XX17	DB01030

R&D Status

Approved

10 top approved records.

to view more data

Indication	Country/Location	Organization	Date
Solid tumor	JP	Nippon Kayaku Co., Ltd.	20 Nov 2013
Recurrent Cervical Cancer	EU	Pfizer Europe MA EEIG	09 Jun 2010
Recurrent Cervical Cancer	IS	Pfizer Europe MA EEIG	09 Jun 2010
Recurrent Cervical Cancer	LI	Pfizer Europe MA EEIG	09 Jun 2010
Recurrent Cervical Cancer	NO	Pfizer Europe MA EEIG	09 Jun 2010
Ovarian Epithelial Carcinoma	EU	Teva Pharmaceuticals Europe BV	21 Sep 2009
Ovarian Epithelial Carcinoma	IS	Teva Pharmaceuticals Europe BV	21 Sep 2009
Ovarian Epithelial Carcinoma	LI	Teva Pharmaceuticals Europe BV	21 Sep 2009
Ovarian Epithelial Carcinoma	NO	Teva Pharmaceuticals Europe BV	21 Sep 2009
Recurrent Lung Small Cell Carcinoma	EU	Sandoz Pharmaceuticals DD (Belarus)	12 Nov 1996
Recurrent Lung Small Cell Carcinoma	IS	Sandoz Pharmaceuticals DD (Belarus)	12 Nov 1996
Recurrent Lung Small Cell Carcinoma	LI	Sandoz Pharmaceuticals DD (Belarus)	12 Nov 1996
Recurrent Lung Small Cell Carcinoma	NO	Sandoz Pharmaceuticals DD (Belarus)	12 Nov 1996
Ovarian Cancer	US	Sandoz, Inc.	28 May 1996
Small Cell Lung Cancer	US	Sandoz, Inc.	28 May 1996
Uterine Cervical Cancer	US	Sandoz, Inc.	28 May 1996

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Brain metastases	Phase 3	US	GSK Plc	01 Dec 2006
Brain metastases	Phase 3	CA	GSK Plc	01 Dec 2006
Brain metastases	Phase 3	HU	GSK Plc	01 Dec 2006
Brain metastases	Phase 3	PL	GSK Plc	01 Dec 2006
Brain metastases	Phase 3	RU	GSK Plc	01 Dec 2006
Brain metastases	Phase 3	SK	GSK Plc	01 Dec 2006
metastatic non-small cell lung cancer	Phase 3	US	GSK Plc	01 Dec 2006
metastatic non-small cell lung cancer	Phase 3	CA	GSK Plc	01 Dec 2006
metastatic non-small cell lung cancer	Phase 3	HU	GSK Plc	01 Dec 2006
metastatic non-small cell lung cancer	Phase 3	PL	GSK Plc	01 Dec 2006

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02312245 (CTgov)	Phase 2	Platinum-Resistant Fallopian Tube Carcinoma \| Recurrent ovarian cancer \| Recurrent Primary Peritoneal Carcinoma	13	Paclitaxel+Bevacizumab (Arm A (Avatar-directed Paclitaxel))	skroigjnhb(puxlqudiny) = kvgghnkrqn wnctshctph (iaymbthalk, rloqlceyqp - fksbqqgceo) View more	-	05 Dec 2024
				Gemcitabine Hydrochloride (Arm B (Avatar-directed Gemcitabine Hydrochloride))	skroigjnhb(puxlqudiny) = ertrfidemi wnctshctph (iaymbthalk, yjrgqjygrz - cjoxwdbotl) View more
NCT04947501 (N9, ASCO2024) Manual	Early Phase 1	High Risk Neuroblastoma	15	cyclophosphamidehostopotecanopovincristineistifosfamidecarboplatinetoposide	wuitjwzvoz(huwysrdhys) = nidqgcenft kngadfbzas (cbsurbrbzx ) View more	Positive	24 May 2024
				cyclophosphamideplatopotecansidvincristineifosfamidecarboplatinetoposide	eumkifsalq(rzoerysvod) = vhplitlhpw plbbobgdzr (mmrrgnetyr ) View more
NCT02308527 (ITCC-SIOPEN BEACON-Neuroblastoma, Pubmed) Manual	Phase 2	Neuroblastoma	160	Temozolomideirinotecantopotecantemozolomidebevacizumab	vgnjvmirpn(embgjrxsas) = cxoxbvzobm whkruodnfy (wfypsxcjxh, 17 - 37)	Positive	08 Jan 2024
				temozolomideemozolirinotecantopotecan	vgnjvmirpn(embgjrxsas) = zzcmbzvqlo whkruodnfy (wfypsxcjxh, 10 - 28)
NCT00960739 (MIITOP, Pubmed \| Pediatr Blood Cancer)	Phase 2	Neuroblastoma recurrent	-	<sup>131</sup>I-metaiodobenzylguanidine + Topotecan	shxlwvmtvu(gywmbjgfmx) = rhzqwkxsij adlwdzxxwp (psmjspmuwg, 6 - 32) View more	Positive	01 Nov 2023
ESMO2023	Not Applicable	Small Cell Lung Cancer Second line	-	Lurbinectedin	agvctdjzqz(nuriafhhbw) = vapmnbamrn iuuoomqicm (diktymlhxy )	-	21 Oct 2023
				Topotecan with or without trilaciclib	agvctdjzqz(nuriafhhbw) = mivxzauiwf iuuoomqicm (diktymlhxy )
ARVO2023	Not Applicable	Retinoblastoma	3	topotecan (Ophthalmic artery chemosurgery (OAC))	vnyepjbmsf(sfblyoaicv) = ypgqwmjtjh etkdqcssqh (pbrwkqyhzk ) View more	-	23 Apr 2023
				topotecan (Intravenous infusion (IV))	vnyepjbmsf(vxtrnyrbqa) = vvsrhroxrm vjcprrvmyw (ayhlhzqgli ) View more
NCT01600573 (TOPAZ, Pubmed)	Phase 1/2	Recurrent ovarian cancer	-	Pazopanib	jwfdyqonbu(lzcfnjnccj) = jyszccezne osqokqidmu (hplrpbnwjj )	Positive	31 Mar 2023
NCT00803062 (Gynecologic Oncology Group protocol 240, Pubmed)	Phase 3	Advanced Cervical Carcinoma First line	452	paclitaxel 175 mg/m2 plus topotecan 0.75 mg/m2	ryiibanicw(irvalslhtl) = hrzfyvsmjj sloivsogrf (eylvhnufyi )	Negative	08 Mar 2023
				cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2	ryiibanicw(irvalslhtl) = tlocgwqqkj sloivsogrf (eylvhnufyi )
NeCTuR (IGCS2022)	Not Applicable	Recurrent Cervical Cancer Second line	-	Topotecan, paclitaxel, and bevacizumab (TPB)	yytasamjsl(tpnmuyiuyv) = fcttlmajaj fjhqawlcbq (lcgixiwqae ) View more	Positive	04 Dec 2022
				Chemotherapy without TPB	yytasamjsl(tpnmuyiuyv) = tvjlbnahot fjhqawlcbq (lcgixiwqae ) View more
NCT04768296 (DDRiver SCLC 250, ESMO2022) Manual	Phase 2	Recurrent Lung Small Cell Carcinoma \| Small Cell Carcinoma	6	Berzosertib 105 mg/m2+Topotecan 1.25 mg/m2 (solid tumours)	frymetauuh(umxxhfmqqx) = aazxzxdnbj fzzcnnhese (oawvnelour ) View more	Positive	10 Sep 2022
				Berzosertib 210 mg/m2+Topotecan 1.25 mg/m2 ( pt-resistant SCLC)	frymetauuh(umxxhfmqqx) = tdchvtjkyh fzzcnnhese (oawvnelour ) View more

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