XmAb®819 for Renal Cell Carcinoma

Recruiting at 9 trial locations

Overseen By Chet Bohac, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Xencor, Inc.

Must not be taking: Antineoplastics, Monoclonal antibodies

Disqualifiers: CNS metastases, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: 2

95 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests XmAb®819, a new drug for kidney cancer patients whose disease has returned or resisted other treatments. It checks if the drug is safe, how the body handles it, and its potential to reduce tumors.

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, you cannot have had systemic cancer treatment within a certain period before starting the trial, so you may need to discuss this with the trial team.

What data supports the effectiveness of the drug XmAb819 for treating renal cell carcinoma?

Research on similar bispecific antibodies, like the A2V CrossMab, shows that targeting two pathways can significantly reduce tumor size and improve treatment outcomes in renal cell carcinoma. Additionally, bispecific antibodies targeting CD3 have been shown to effectively direct immune cells to attack cancer cells, suggesting potential for XmAb819. ^{1 2 3 4 5}

What safety data exists for XmAb®819 or similar bispecific antibodies in humans?

In a study involving a bispecific antibody similar to XmAb®819, some patients experienced temporary side effects like leukopenia (a drop in white blood cells) and elevated levels of certain proteins in the blood after treatment. The maximum tolerated dose was identified, indicating careful monitoring is needed during treatment. ^{1 2 5 6 7}

What makes the drug XmAb819 unique for treating renal cell carcinoma?

XmAb819 is a bispecific antibody that targets both ENPP3 on tumor cells and CD3 on T-cells, which helps direct the body's immune system to attack the cancer cells. This dual-targeting approach is different from traditional treatments that typically focus on a single target, potentially enhancing the immune response against the tumor. ^{1 2 5 7 8}

Research Team

Chet Bohac, MD

Principal Investigator

Xencor, Inc.

Eligibility Criteria

This trial is for adults with advanced clear cell renal cell carcinoma who have seen their cancer return or not respond to standard treatments. They must be relatively healthy (ECOG status 0 or 1), have a tumor sample available, and measurable disease. People can't join if they've had certain recent cancers, brain metastases, serious allergies to monoclonal antibodies, autoimmune diseases, or significant infections recently.

Inclusion Criteria

My cancer can be measured by scans and has grown in previously treated areas.

I am fully active or can carry out light work.

My kidney cancer has returned and worsened despite treatment.

Exclusion Criteria

I have another cancer that is getting worse or was treated in the last 2 years.

I have an autoimmune disease but it's either vitiligo, type 1 diabetes, manageable thyroid issues, skin conditions not needing systemic treatment, or arthritis treated without strong medication.

I haven't taken cancer drugs within a period before starting the study treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation (Part A)

Establish the dosing schedule for XmAb819 administered IV and SC, including priming and step-up doses

8 weeks

Weekly visits for dose adjustments and monitoring

Dose Expansion (Part B)

Administer XmAb819 IV or SC to further evaluate safety, tolerability, and preliminary antitumor activity

8 weeks

Bi-weekly visits for treatment and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 weeks

2 visits (in-person)

Treatment Details

Interventions

• XmAb819

Trial Overview The study tests XmAb®819 given through IV or SC injections in patients with relapsed/refractory kidney cancer. It aims to find the safest and most effective dose that shows biological activity against the cancer.

Participant Groups

Group I: Dose Escalation and Expansion Experimental Treatment 1 Intervention

Dose Escalation (Part A): Part A will establish the dosing schedule for XmAb819 administered IV and the dosing schedule of XmAb819 administered SC in subjects with ccRCC. The dosing schedule includes the priming dose, step-up priming dose(s), the minimum safe and biologically active dose. Dose Expansion (Part B): Part B-1 may administer XmAb819 IV, and Part B-2 may administer XmAb819 SC.

Who Is Running the Clinical Trial?

Xencor, Inc.

Lead Sponsor

Trials

31

Recruited

2,500+

Findings from Research

The study developed an effective pretargeting strategy for renal cell carcinoma (RCC) using a bispecific monoclonal antibody (bsMAb), which showed high tumor uptake of a radiolabeled peptide compared to other methods.

Optimal conditions for the pretargeting strategy were identified, with a 72-hour interval for the bsMAb IgG and a 4-hour interval for the bsMAb F(ab')(2), demonstrating that both forms of the bsMAb can achieve efficient tumor targeting without affecting the retention of the radiolabel.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of IgG and F(ab')2 fragments of bispecific anti-RCCxanti-DTIn-1 antibody for pretargeting purposes. van Schaijk, FG., Boerman, OC., Soede, AC., et al.[2018]

The novel bispecific antibody A2V CrossMab, targeting both Angiopoietin-2 and VEGF, significantly reduced tumor volume and vessel density in renal cell carcinoma compared to treatments targeting either factor alone.

A2V CrossMab also led to a significant down-regulation of angiogenesis-related genes, indicating its potential for enhanced anti-tumor efficacy in RCC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Ang-2-VEGF-A Bispecific Antibody in Renal Cell Carcinoma. Bessho, H., Wong, B., Huang, D., et al.[2015]

The bispecific antibody construct (bAb) targeting both CD3 and EGFR effectively induced significant cell lysis in EGFR-positive tumor cells at very low concentrations (1 ng/ml), demonstrating its potential efficacy in targeting cancer cells.

However, the bAb also caused lysis of normal cells expressing EGFR, indicating a need for careful consideration of safety in future clinical trials, as it may affect healthy tissues alongside tumor cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of tumour cell lysis by a bispecific antibody recognising epidermal growth factor receptor (EGFR) and CD3. Knuth, A., Bernhard, H., Jäger, E., et al.[2019]

Pretargeting with a bispecific antibody and a (90)Y-peptide significantly increased the amount of radioactivity delivered to colorectal tumors, resulting in a 2.5-fold increase in tumor radioactivity compared to conventional (90)Y-IgG treatment.

This method not only improved therapeutic efficacy, leading to better survival rates and tumor ablation, but also reduced hematologic toxicity, making it a safer option at higher doses compared to traditional radioimmunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic advantage of pretargeted radioimmunotherapy using a recombinant bispecific antibody in a human colon cancer xenograft. Karacay, H., Brard, PY., Sharkey, RM., et al.[2006]

In a phase I trial involving renal cell carcinoma patients, the bispecific monoclonal antibody BIS-1 demonstrated a maximum tolerated dose of 5 micrograms/kg, with acute but transient toxicity observed at higher doses.

Treatment with BIS-1 F(ab')2 fragments led to increased antitumor activity against EGP-2, particularly at the 3 and 5 micrograms/kg doses, suggesting a potential for enhanced immune response against cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bispecific monoclonal antibodies for intravenous treatment of carcinoma patients: immunobiologic aspects. Kroesen, BJ., Janssen, RA., Buter, J., et al.[2016]

The study demonstrated that pretargeting with the bispecific monoclonal antibody TF2 followed by the radiolabelled hapten peptide IMP288 allows for rapid and selective targeting of tumors in patients with metastatic colorectal cancer, achieving high tumor-to-tissue ratios within 24 hours.

The method was found to be safe, with high doses of (177)Lu-IMP288 being well tolerated, although some patients experienced manageable infusion reactions and transient thrombocytopenia, indicating a favorable safety profile for this innovative approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results. Schoffelen, R., Boerman, OC., Goldenberg, DM., et al.[2022]

The bispecific monoclonal antibody OC/TR shows specific localization in Hela tumor xenografts in nude mice, indicating its potential for targeted cancer therapy despite having a lower affinity than the parental MOv18 antibody.

Although OC/TR has reduced tumor uptake compared to MOv18, it still meets the initial requirement for effective tumor targeting, suggesting it could be a promising therapeutic option, pending further investigation into its interaction with human T-cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumour targeting of the anti-ovarian carcinoma x anti-CD3/TCR bispesific monoclonal antibody OC/TR and its parental MOv18 antibody in experimental ovarian cancer. Boerman, OC., Tibben, JG., Massuger, LF., et al.[2015]

The monoclonal antibody G250 shows preferential localization to renal-cell carcinoma (RCC) xenografts in mice, with 27.4% of the injected dose per gram found in tumors 24 hours after injection, indicating its potential effectiveness for targeting RCC.

Using F(ab')2 fragments of G250 resulted in higher tumor-to-blood ratios, suggesting that these smaller fragments may be more suitable for diagnostic purposes in patients, as tumor uptake is more influenced by size than binding affinity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Localization of monoclonal antibody G250 and bispecific monoclonal antibody CD3/G250 in human renal-cell carcinoma xenografts: relative effects of size and affinity. van Dijk, J., Zegveld, ST., Fleuren, GJ., et al.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Comparison of IgG and F(ab')2 fragments of bispecific anti-RCCxanti-DTIn-1 antibody for pretargeting purposes. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Effect of Ang-2-VEGF-A Bispecific Antibody in Renal Cell Carcinoma. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Induction of tumour cell lysis by a bispecific antibody recognising epidermal growth factor receptor (EGFR) and CD3. [2019]

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

Therapeutic advantage of pretargeted radioimmunotherapy using a recombinant bispecific antibody in a human colon cancer xenograft. [2006]

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

Bispecific monoclonal antibodies for intravenous treatment of carcinoma patients: immunobiologic aspects. [2016]

6. England pubmed.ncbi.nlm.nih.gov

Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results. [2022]

7. Greece pubmed.ncbi.nlm.nih.gov

Tumour targeting of the anti-ovarian carcinoma x anti-CD3/TCR bispesific monoclonal antibody OC/TR and its parental MOv18 antibody in experimental ovarian cancer. [2015]

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

Localization of monoclonal antibody G250 and bispecific monoclonal antibody CD3/G250 in human renal-cell carcinoma xenografts: relative effects of size and affinity. [2019]