DS-1103a + T-DXd for Advanced Cancer
Recruiting in Palo Alto (17 mi)
+9 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Daiichi Sankyo
Must not be taking: Corticosteroids, Immunosuppressives
Disqualifiers: Myocardial infarction, ILD, CNS metastases, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This study will evaluate the safety and efficacy of DS-1103a combination therapy in patients with advanced solid tumors.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications. However, you cannot use chronic systemic corticosteroids or other immunosuppressive medications during the study.
What makes the drug DS-1103a + T-DXd unique for advanced cancer?
The drug DS-1103a + T-DXd is unique because it combines an anti-SIRPα monoclonal antibody (DS-1103a) with T-DXd, potentially offering a novel mechanism of action by targeting specific proteins involved in cancer cell survival and immune evasion, which may not be addressed by existing treatments.
12345Eligibility Criteria
Adults over 18 with advanced solid tumors, specifically HER2-expressing or mutated, who've had prior treatment without success. They must have measurable lesions and be in good health with proper organ function. Women of childbearing age need a negative pregnancy test and agree to birth control; men must also use birth control.Inclusion Criteria
Sign and date the informed consent form (ICF) prior to the start of any study-specific qualification procedures
Presence of at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI)
I am a man who is sterile or my partner uses effective birth control.
+12 more
Exclusion Criteria
I am pregnant, breastfeeding, or planning to become pregnant.
I have been treated with anti-CD47 or anti-SIRPα therapy before.
Has a QTcF prolongation to >470 ms (females) or >450 ms (males)
+21 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Participants receive DS-1103a and T-DXd in a dose-escalating manner to assess safety and efficacy
Up to 44 months
Cycles 1, 2, and 4: Days 1, 2, 4, 8, 15; Cycle 3: Days 1, 8, 15; Cycle 5 and beyond: Day 1 (each cycle is 21 days)
Dose Expansion
Participants receive DS-1103a at the recommended dose for expansion in combination with T-DXd
Up to 44 months
Cycles 1 and 3: Days 1, 2, 4, 8, 15; Cycle 2: Days 1, 8, 15; Cycle 4 and beyond: Day 1 (each cycle is 21 days)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing DS-1103a combined with T-DXd for safety and effectiveness against advanced solid tumors. Participants will receive this combination therapy to see how well it works compared to current treatments.
2Treatment groups
Experimental Treatment
Group I: Dose Expansion: DS-1103a + T-DXdExperimental Treatment2 Interventions
Participants with HER2-low expressing breast cancer who will receive an IV infusion of DS-1103a at the recommended dose for expansion (RDE) in combination with T-DXd 5.4 mg/kg Q3W starting on Cycle 1 Day 1.
Group II: Dose Escalation: DS-1103a + T-DXdExperimental Treatment2 Interventions
Participants with HER2-expressing or HER2-mutant advanced metastatic solid tumors who will receive an intravenous (IV) infusion of DS-1103a (starting dose of 100 mg) every 3 weeks (Q3W) starting on Cycle 1 Day 1. Starting on Cycle 2 Day 1 and on Day 1 of each subsequent cycle, participants will also receive T-DXd Q3W at a dose of 5.4 mg/kg.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Novant Health Clinical Research, LLCCharlotte, NC
Emory University School of MedicineAtlanta, GA
Lifespan Cancer InstituteProvidence, RI
Princess Margaret Cancer Centre, University Health NetworkToronto, Canada
More Trial Locations
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Who Is Running the Clinical Trial?
Daiichi SankyoLead Sponsor
Daiichi Sankyo, Inc.Lead Sponsor
AstraZenecaIndustry Sponsor
References
Cytoplasmic SIRT1 promotes paclitaxel resistance in ovarian carcinoma through increased formation and survival of polyploid giant cancer cells. [2023]Therapeutic resistance is a notable cause of death in patients with ovarian carcinoma. Polyploid giant cancer cells (PGCCs), commonly arising in tumor tissues following chemotherapy, have recently been considered to contribute to drug resistance. As a type III deacetylase, Sirtuin1 (SIRT1) plays essential roles in the cell cycle, cellular senescence, and drug resistance. Accumulating evidence has suggested that alteration in its subcellular localization via nucleocytoplasmic shuttling is a critical process influencing the functions of SIRT1. However, the roles of SIRT1 subcellular localization in PGCC formation and subsequent senescence escape remain unclear. In this study, we compared the differences in the polyploid cell population and senescence state of PGCCs following paclitaxel treatment between tumor cells overexpressing wild-type SIRT1 (WT SIRT1) and those expressing nuclear localization sequence (NLS)-mutated SIRT1 (SIRT1NLSmt ). We investigated the involvement of cytoplasmic SIRT1 in biological processes and signaling pathways, including the cell cycle and cellular senescence, in ovarian carcinoma cells' response to paclitaxel treatment. We found that the SIRT1NLSmt tumor cell population contained more polyploid cells and fewer senescent PGCCs than the SIRT1-overexpressing tumor cell population. Comparative proteomic analyses using co-immunoprecipitation (Co-IP) combined with liquid chromatography-mass spectrometry (LC-MS)/MS showed the differences in the differentially expressed proteins related to PGCC formation, cell growth, and death, including CDK1 and CDK2, between SIRT1NLSmt and SIRT1 cells or PGCCs. Our results suggested that ovarian carcinoma cells utilize polyploidy formation as a survival mechanism during exposure to paclitaxel-based treatment via the effect of cytoplasmic SIRT1 on PGCC formation and survival, thereby boosting paclitaxel resistance. © 2023 The Pathological Society of Great Britain and Ireland.
Inhibition of epithelial cell migration and Src/FAK signaling by SIRT3. [2018]Metastasis remains the leading cause of cancer mortality, and reactive oxygen species (ROS) signaling promotes the metastatic cascade. However, the molecular pathways that control ROS signaling relevant to metastasis are little studied. Here, we identify SIRT3, a mitochondrial deacetylase, as a regulator of cell migration via its control of ROS signaling. We find that, although mitochondria are present at the leading edge of migrating cells, SIRT3 expression is down-regulated during migration, resulting in elevated ROS levels. This SIRT3-mediated control of ROS represses Src oxidation and attenuates focal adhesion kinase (FAK) activation. SIRT3 overexpression inhibits migration and metastasis in breast cancer cells. Finally, in human breast cancers, SIRT3 expression is inversely correlated with metastatic outcome and Src/FAK signaling. Our results reveal a role for SIRT3 in cell migration, with important implications for breast cancer progression.
Radiosensitization effect of overexpression of adenovirus-mediated SIRT6 on A549 non-small cell lung cancer cells. [2022]To explore the radiosensitization effect of overexpression of silent information regulator 6 (SIRT6) on A549 non-small cell lung cancer (NSCLC) cells.
Generation of a novel model of primary human cell senescence through Tenovin-6 mediated inhibition of sirtuins. [2020]Cell senescence, a state of cell cycle arrest and altered metabolism with enhanced pro-inflammatory secretion, underlies at least some aspects of organismal ageing. The sirtuin family of deacetylases has been implicated in preventing premature ageing; sirtuin overexpression or resveratrol-mediated activation of sirtuins increase longevity. Here we show that sirtuin inhibition by short-term, low-dose treatment with the experimental anti-cancer agent Tenovin-6 (TnV6) induces cellular senescence in primary human fibroblasts. Treated cells cease proliferation and arrest in G1 of the cell cycle, with elevated p21 levels, DNA damage foci, high mitochondrial and lysosomal load and increased senescence-associated β galactosidase activity, together with actin stress fibres and secretion of IL-6 (indicative of SASP upregulation). Consistent with a histone deacetylation role of SIRT1, we find nuclear enlargement, possibly resulting from chromatin decompaction on sirtuin inhibition. These findings highlight TnV6 as a drug that may be useful in clinical settings where acute induction of cell senescence would be beneficial, but also provide the caveat that even supposedly non-genotoxic anticancer drugs can have unexpected and efficacy-limiting impacts on non-transformed cells.
Cytoplasmic SIRT1 inhibits cell migration and invasion by impeding epithelial-mesenchymal transition in ovarian carcinoma. [2020]Sirtuin1 (SIRT1) is a mammalian NAD+-dependent type III deacetylase that plays paramount roles in diverse cellular processes. The nucleocytoplasmic shuttling of SIRT1 was discovered more than a decade ago, but the roles of subcellular SIRT1 localization in tumor progression remain unclear. Here, we report that cytoplasmic SIRT1 acts as a tumor suppressor in ovarian carcinoma. By creating ovarian carcinoma cell lines overexpressing wild-type SIRT1 and nuclear localization signals (NLSs) mutated SIRT1 together with both unbiased proteomic and acetylomic approaches and Transwell assays, we identified that mutations in the NLS sequences prevented SIRT1 from entering the nucleus, resulting in the predominant cytoplasmic localization of SIRT1; the cytoplasmic localization of SIRT1 suppressed the mesenchymal program, activated the epithelial program, and inhibited the migration and invasion of tumor cells, thus providing experimental evidence that SIRT1 functions as a tumor suppressor or oncogene may depend on its subcellular localization. Altogether, our findings may highlight a novel role of cytoplasmic SIRT1 in ovarian carcinoma, providing new possible insights for studies investigating the role of SIRT1 in tumor progression.