XmAb541 for Cancer

Recruiting at 8 trial locations

Overseen By Mira Kistler, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Xencor, Inc.

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Autoimmune disease, CNS metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

212 Participants Needed

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 the 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. ^{1 2 3 4 5}

What 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. ^{4 6 7 8 9}

Eligibility 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

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)

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

Treatment Details

Interventions

• XmAb541

Trial Overview 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.

Participant Groups

Group I: Dose escalation and Dose Expansion of XmAb541 Experimental Treatment 1 Intervention

Intravenous or Subcutaneous administration

Who Is Running the Clinical Trial?

Xencor, Inc.

Lead Sponsor

Trials

31

Recruited

2,500+

Findings from Research

The anti-claudin (CLDN)-4 antibody, 4D3, enhances the effectiveness of paclitaxel (PTX) in treating triple negative breast cancer (TNBC) by increasing PTX concentration in cancer cells and promoting apoptosis, as demonstrated in both cell lines and mouse models.

4D3 not only improves the antitumor effects of PTX but also reduces tumor-associated M2 macrophages and stemness, suggesting it could be a valuable addition to existing TNBC therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting claudin-4 enhances chemosensitivity in breast cancer. Luo, Y., Kishi, S., Sasaki, T., et al.[2020]

CLDN6 is a promising target for cancer treatment due to its high expression in various cancers (like ovarian and testicular) and low expression in normal adult tissues, making it a potential safe target for therapies.

Several types of anticancer drugs, including antibody-drug conjugates and CAR-T therapies, are being developed to specifically target CLDN6, which may help overcome challenges like tumor growth and chemoresistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Advances of Claudin6-targeting drugs in cancer therapy]. Li, G., Bi, Y., Hao, R., et al.[2023]

BNT141, an mRNA therapeutic encoding the antibody IMAB362/Zolbetuximab, shows a stable pharmacokinetic profile and effectively targets CLDN18.2-positive cancer cells, demonstrating comparable cytotoxicity to the recombinant protein in preclinical models.

In animal studies, BNT141 was found to be safe, with no observed mortality or significant toxicity, and a phase 1/2 clinical trial has been initiated to evaluate its efficacy in advanced solid cancers expressing CLDN18.2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody. Bähr-Mahmud, H., Ellinghaus, U., Stadler, CR., et al.[2023]

ENMD-2076 shows antitumor activity in preclinical models of triple-negative breast cancer (TNBC) with p53 mutations, inducing apoptosis in sensitive models and correlating with increased levels of p53 and p73.

Resistance to ENMD-2076 is linked to a senescent cell phenotype and a switch in TNBC subtype from luminal androgen receptor to basal-like, suggesting that treatment may alter tumor biology and highlighting the need for further investigation in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Ionkina, AA., Tentler, JJ., Kim, J., et al.[2020]

In preclinical models of triple-negative breast cancer (TNBC), the novel anti-cancer agent RX-5902 significantly enhanced the effectiveness of immune checkpoint inhibitors (anti-CTLA-4 and anti-PD-1), leading to reduced tumor growth and increased activation of T cells in the tumor environment.

The combination of RX-5902 with nivolumab (an anti-PD-1 inhibitor) resulted in a notable increase in activated tumor-infiltrating lymphocytes and systemic granzyme B production, suggesting that RX-5902 not only boosts anti-tumor activity but also improves the immune response against TNBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer. Tentler, JJ., Lang, J., Capasso, A., et al.[2021]

In a study of 143 breast cancer patients, CMTM6 expression was found to be significantly higher in triple-negative breast cancer (TNBC) compared to HER2-driven breast cancer, suggesting its potential role in TNBC pathology.

CMTM6 expression was correlated with PD-L1 levels in TNBC and was identified as an independent risk factor for poor progression-free survival (PFS), indicating its potential as a biomarker for predicting patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The association of CMTM6 expression with prognosis and PD-L1 expression in triple-negative breast cancer. Tian, Y., Sun, X., Cheng, G., et al.[2022]

Complement component 3 (C3) is significantly upregulated in paclitaxel-resistant non-small cell lung cancer (NSCLC) cells, and reducing C3 levels can enhance the effectiveness of paclitaxel therapy by promoting cancer cell apoptosis.

C3 functions in the nucleus to repress the expression of GADD45A, a gene important for cell growth inhibition and apoptosis, suggesting that targeting C3 could be a novel strategy to overcome resistance to chemotherapy in NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer. Wang, X., Hao, Y., Chen, J., et al.[2023]

MXD3 is found to be abnormally expressed in nearly all cancer types studied, and its levels are linked to tumor progression, metastasis, and poorer patient prognoses, indicating its potential role as a biomarker for cancer outcomes.

The study suggests that MXD3 contributes to immune evasion in tumors by affecting T-cell infiltration and response, and its expression levels can predict responses to immunotherapy, making it a promising target for therapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types. Wu, SY., Lin, KC., Lawal, B., et al.[2021]

CMTM3 is significantly down-regulated in 84% of clear cell renal cell carcinoma (ccRCC) tissues, suggesting its potential role as a tumor suppressor in this type of cancer.

Restoring CMTM3 expression in ccRCC cells led to a marked decrease in cell proliferation, migration, and anchorage-independent growth, indicating that targeting CMTM3 could be a promising therapeutic strategy for ccRCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CMTM3 is frequently reduced in clear cell renal cell carcinoma and exhibits tumor suppressor activities. Xie, J., Yuan, Y., Liu, Z., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Targeting claudin-4 enhances chemosensitivity in breast cancer. [2020]

2. China pubmed.ncbi.nlm.nih.gov

[Advances of Claudin6-targeting drugs in cancer therapy]. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Preclinical characterization of an mRNA-encoded anti-Claudin 18.2 antibody. [2023]

4. Switzerland pubmed.ncbi.nlm.nih.gov

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]

5. England pubmed.ncbi.nlm.nih.gov

RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer. [2021]

6. China pubmed.ncbi.nlm.nih.gov

The association of CMTM6 expression with prognosis and PD-L1 expression in triple-negative breast cancer. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Nuclear complement C3b promotes paclitaxel resistance by assembling the SIN3A/HDAC1/2 complex in non-small cell lung cancer. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

MXD3 as an onco-immunological biomarker encompassing the tumor microenvironment, disease staging, prognoses, and therapeutic responses in multiple cancer types. [2021]

9. Italy pubmed.ncbi.nlm.nih.gov

CMTM3 is frequently reduced in clear cell renal cell carcinoma and exhibits tumor suppressor activities. [2021]