XmAb541 for Cancer
Recruiting in Palo Alto (17 mi)
+6 other locations
Age: Any Age
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Xencor, Inc.
Must not be taking: Corticosteroids, Immunosuppressives
Disqualifiers: Autoimmune disease, CNS metastases, others
No Placebo Group
Trial Summary
What is the purpose of this trial?The primary purpose of this study is to determine whether the investigational drug XmAb541 is safe and well tolerated, and to determine an optimal and safe dose(s) for further study. The study will also evaluate effect of XmAb541 on tumor outcomes.
Will I have to stop taking my current medications?
The trial protocol does not specify if you need to stop taking your current medications. However, if you are on corticosteroids or other immunosuppressive medications, you may need to stop them at least 14 days before starting the study drug.
What data supports the effectiveness of the drug XmAb541 (CLDN6 x CD3) for cancer?
Research shows that targeting CLDN6, a protein found in certain cancers, can be effective because it is highly expressed in tumors but not in normal tissues. Drugs targeting CLDN6, like XmAb541, are being developed to potentially stop cancer growth and spread.
12345What makes the drug XmAb541 unique for cancer treatment?
XmAb541 is a novel cancer treatment that targets both CLDN6 (a protein often found on cancer cells) and CD3 (a protein on T cells, which are part of the immune system), potentially enhancing the immune system's ability to attack cancer cells. This dual-targeting approach is different from traditional treatments that may not specifically engage the immune system in this way.
46789Eligibility Criteria
Adults with advanced solid tumors, specifically ovarian, fallopian tube, peritoneal cancer, endometrial cancer or germ cell tumors (GCT), who have progressive disease despite standard treatments. Participants must be over 18 years old (15 for GCT), have good organ function and a life expectancy of at least 3 months.Inclusion Criteria
My liver, kidneys, thyroid, and bone marrow are working well.
I am able to care for myself and perform daily activities.
Life expectancy ≥ 3 months
+4 more
Exclusion Criteria
Active known or suspected autoimmune disease
Positive test for hepatitis C RNA
Positive test for hepatitis B surface antigen or hepatitis B core antibody (hBcAb)
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation and Expansion
Participants receive XmAb541 to evaluate safety, tolerability, and optimal dosing
Up to 2 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing the safety and tolerability of XmAb541 to find the best dose for future studies. It will also assess how well XmAb541 works against these types of cancers.
1Treatment groups
Experimental Treatment
Group I: Dose escalation and Dose Expansion of XmAb541Experimental Treatment1 Intervention
Intravenous or Subcutaneous administration
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Karmanos Cancer InstituteDetroit, MI
University of VirginiaCharlottesville, VA
The John Theruer Cancer Center at Hackensack University Medical CenterHackensack, NJ
OU Health Stephenson Cancer CenterOklahoma City, OK
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
Xencor, Inc.Lead Sponsor
References
Targeting claudin-4 enhances chemosensitivity in breast cancer. [2020]Triple negative breast cancer (TNBC) is characterized by highly aggressive phenotype, limited treatment options and a poor prognosis. In the present study, we examined the therapeutic effect of anti-claudin (CLDN)-4 extracellular domain antibody, 4D3, on TNBC. When the expression of CLDN4 and CLDN1 in invasive ductal carcinoma (IDC) was examined in 114 IDC (78 cases from 2004 to 2009 in a single center and 36 cases of tissues array), CLDN1 had lower expression than CLDN4 and was correlated with histological grade. In contrast, expression of CLDN4 was correlated with histological grade, receptor subtype, and stage. CLDN4 expression in human IDC cell lines MCF-7 (luminal subtype) and MDA-468 (TNBC) was at the same level. In both cells, paclitaxel (PTX)-induced growth suppression was enhanced by 4D3. Furthermore, 4D3 increased both intracellular PTX concentration (in both cells) and apoptosis. In the mouse model, 4D3 promoted the antitumor effect of PTX on subcutaneous tumors and reduced lung metastasis. The combination of PTX and 4D3 reduced M2 macrophages and mesenchymal stem cells in the tumor. 4D3 also reduced stemness of the tumors and increased the intratumoral pH. Moreover, concurrent treatment with 4D3, PTX and tamoxifen, or with PTX and tamoxifen in MDA-468 also showed the same level of antitumor activity and survival as MCF-7. Furthermore, in a bone metastasis model, combination of PTX and bisphosphonate with 4D3 promoted tumor growth in both cells. Thus, CLDN4 targeting of the antibody facilitated existing therapeutic effects.
[Advances of Claudin6-targeting drugs in cancer therapy]. [2023]CLDN6 is a member of the CLDNs family that is specifically and highly expressed in cancers such as ovarian, testicular, endocervical, liver and lung adenocarcinoma, but hardly expressed in adult normal tissues. CLDN6 is able to activate multiple signaling pathways, which take part in the development and progression of cancer, including promoting tumor growth, migration and invasion, and promoting chemoresistance in cancer. In recent years, CLDN6 has received much attention as a novel target for cancer therapeutics. Many types of anticancer drugs targeting CLDN6 have been developed, including antibody-conjugated drugs (ADC), monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T-cell immunotherapy (CAR-T). This paper briefly summarizes the structure, expression and function of CLDN6 in tumors, and reviews the current status and ideas of developing targeted CLDN6 anticancer drugs.
Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody. [2023]IMAB362/Zolbetuximab, a first-in-class IgG1 antibody directed against the cancer-associated gastric-lineage marker CLDN18.2, has recently been reported to have met its primary endpoint in two phase 3 trials as a first-line treatment in combination with standard of care chemotherapy in CLDN18.2-positive Her2 negative advanced gastric cancer. Here we characterize the preclinical pharmacology of BNT141, a nucleoside-modified RNA therapeutic encoding the sequence of IMAB362/Zolbetuximab, formulated in lipid nanoparticles (LNP) for liver uptake. We show that the mRNA-encoded antibody displays a stable pharmacokinetic profile in preclinical animal models, mediates CLDN18.2-restricted cytotoxicity comparable to IMAB362 recombinant protein and inhibits human tumor xenograft growth in immunocompromised mice. BNT141 administration did not perpetrate mortality, clinical signs of toxicity, or gastric pathology in animal studies. A phase 1/2 clinical trial with BNT141 mRNA-LNP has been initiated in advanced CLDN18.2-expressing solid cancers (NCT04683939).
Efficacy and Molecular Mechanisms of Differentiated Response to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Models of p53-Mutated Triple-Negative Breast Cancer. [2020]Triple-negative breast cancer (TNBC) is a subtype associated with poor prognosis and for which there are limited therapeutic options. The purpose of this study was to evaluate the efficacy of ENMD-2076 in p53-mutated TNBC patient-derived xenograft (PDX) models and describe patterns of terminal cell fate in models demonstrating sensitivity, intrinsic resistance, and acquired resistance to ENMD-2076.
RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer. [2021]Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear β-catenin signaling. The purpose of this study was to evaluate the ability of β-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC.
The association of CMTM6 expression with prognosis and PD-L1 expression in triple-negative breast cancer. [2022]Immune checkpoint inhibitors play a vital role in triple-negative breast cancer (TNBC) immunotherapy. A recent study showed that chemokine-like factor (CKLF)-like MARVEL transmembrane domain containing 6 (CMTM6) has a crucial role in programmed death-ligand 1 (PD-L1) stability. The aim of this study was to investigate the relationship between CMTM6 and PD-L1 in TNBC and the association with clinical characteristics.
Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer. [2023]In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance.
MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types. [2021]MAX dimerization (MXD) protein 3 (MXD3) is a member of the MXD family of basic-helix-loop-helix-leucine-zipper (bHLHZ) transcription factors that plays pivotal roles in cell cycle progression and cell proliferation. However, there is insufficient scientific evidence on the pathogenic roles of MXD3 in various cancers and whether MXD3 plays a role in the immuno-oncology context of the tumor microenvironment, pathogenesis, prognosis, and therapeutic response of different tumors through certain common molecular mechanisms; thus, we saw a need to conduct the present in silico pan-cancer study. Using various computational tools, we interrogated the role of MXD3 in tumor immune infiltration, immune evasion, tumor progression, therapy response, and prognosis of cohorts from various cancer types. Our results indicated that MXD3 was aberrantly expressed in almost all The Cancer Genome Atlas (TCGA) cancer types and subtypes and was associated with the tumor stage, metastasis, and worse prognoses of various cohorts. Our results also suggested that MXD3 is associated with tumor immune evasion via different mechanisms involving T-cell exclusion in different cancer types and by tumor infiltration of immune cells in thymoma (THYM), liver hepatocellular carcinoma (LIHC), and head and neck squamous cell carcinoma (HNSC). Methylation of MXD3 was inversely associated with messenger (m)RNA expression levels and mediated dysfunctional T-cell phenotypes and worse prognoses of cohorts from different cancer types. Finally, we found that genetic alterations and oncogenic features of MXD3 were concomitantly associated with deregulation of the DBN1, RAB24, SLC34A1, PRELID1, LMAN2, F12, GRK6, RGS14, PRR7, and PFN3 genes and were connected to phospholipid transport and ion homeostasis. Our results also suggested that MXD3 expression is associated with immune or chemotherapeutic outcomes in various cancers. In addition, higher MXD3 expression levels were associated with decreased sensitivity of cancer cell lines to several mitogen-activated protein kinase kinase (MEK) inhibitors but led to increased activities of other kinase inhibitors, including Akt inhibitors. Interestingly, MXD3 exhibited higher predictive power for response outcomes and overall survival of immune checkpoint blockade sub-cohorts than three of seven standardized biomarkers. Altogether, our study strongly suggests that MXD3 is an immune-oncogenic molecule and could serve as a biomarker for cancer detection, prognosis, therapeutic design, and follow-up.
CMTM3 is frequently reduced in clear cell renal cell carcinoma and exhibits tumor suppressor activities. [2021]CKLF-like MARVEL transmembrane domain containing member 3 (CMTM3) is silenced in many kinds of cancers and inhibits tumor cells growth. We investigated the expression and role of CMTM3 in clear cell renal cell carcinoma (ccRCC).