XmAb®819 for Renal Cell Carcinoma
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: Xencor, Inc.
Must not be taking: Antineoplastics, Monoclonal antibodies
Disqualifiers: CNS metastases, Autoimmune disease, others
No Placebo Group
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 XmAb819.12345
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.12567
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.12578
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.
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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.
See 5 more
Trial 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 (Monoclonal Antibodies)
Trial OverviewThe 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
1Treatment groups
Experimental Treatment
Group I: Dose Escalation and ExpansionExperimental Treatment1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Duke UniversityDurham, NC
Fred Hutchinson Cancer CenterSeattle, WA
Fox Chase Cancer CenterPhiladelphia, PA
Winship Cancer Institute of Emory UniversityAtlanta, GA
More Trial Locations
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Who Is Running the Clinical Trial?
Xencor, Inc.Lead Sponsor
References
Comparison of IgG and F(ab')2 fragments of bispecific anti-RCCxanti-DTIn-1 antibody for pretargeting purposes. [2018]An effective pretargeting strategy was developed for renal cell carcinoma (RCC) based on a biologically produced bispecific monoclonal antibody: anti-RCCxanti-DTPA(In) (bsMAb: G250xDTIn-1). Tumour uptake of a (111)In-labelled bivalent peptide after pretargeting with bsMAb G250xDTIn-1 was relatively high compared with that in other pretargeting systems using chemically coupled F(ab')(2) fragments. Here, we investigated the effect of the bsMAb form in the pretargeting strategy.
Effect of Ang-2-VEGF-A Bispecific Antibody in Renal Cell Carcinoma. [2015]The blockade of VEGF pathway has been clinically validated as an initial treatment for renal cell carcinoma (RCC). Angiopoietin-2 (Ang-2) has been indicated as a key regulator for angiogenesis escape. The effect of a novel bispecific antibody (A2V CrossMab) against both Ang-2 and VEGF was investigated in comparison with either factor. A2V CrossMab significantly reduced tumor volume, vessel density, and interstitial fluid pressure compared to either monotherapy of anti-VEGF or anti-Ang-2. Host-derived angiogenesis-related genes have been significantly down-regulated in A2V CrossMab group. These data demonstrate that A2V CrossMab has additive anti-tumor effect for the treatment of RCC.
Induction of tumour cell lysis by a bispecific antibody recognising epidermal growth factor receptor (EGFR) and CD3. [2019]A bispecific antibody construct (bAb) recognising CD3 and epidermal growth factor receptor (EGFR) was studied in vitro. Human peripheral blood lymphocytes (PBL), pre-activated with monoclonal antibody OKT-3 or with irradiated tumour cells, were armed with the bAb construct and targeted to autologous and allogeneic tumour target cells in culture. bAb EGFR x CD3 promoted significant cytolysis even at a concentration of 1 ng/ml. The specificity of target cell lysis was provided by the EGFR specificity of the bAb, as tumour cells negative for EGFR were not lysed. However, not only EGFR-positive tumour cells but also EGFR-positive normal cells were killed. Human renal cancer cell lines and the normal autologous kidney cell cultures expressing the same level of EGFR molecules were lysed to a similar extent. These results may contribute toward the planning of future clinical trials with such bAb.
Therapeutic advantage of pretargeted radioimmunotherapy using a recombinant bispecific antibody in a human colon cancer xenograft. [2006]To assess if pretargeting, using a combination of a recombinant bispecific antibody (bsMAb) that binds divalently to carcinoembryonic antigen (CEA) and monovalently to the hapten histamine-succinyl-glycine and a (90)Y-peptide, improves therapeutic efficacy in a human colon cancer-nude mouse xenograft compared with control animals given (90)Y-humanized anti-CEA immunoglobulin G (IgG).
Bispecific monoclonal antibodies for intravenous treatment of carcinoma patients: immunobiologic aspects. [2016]Immunobiologic parameters measured during a phase I trial of intravenously (i.v.) administered bispecific monoclonal antibodies (BsmAb) in renal cell carcinoma (RCC) patients are described. The BsmAb used, BIS-1, is reactive with a pancarcinoma-associated 38 kDa transmembrane glycoprotein, EGP-2, as well with the CD3 complex. Patients received during a 2 h i.v. infusion F(ab')2 fragments of BIS-1 at doses of 1, 3, or 5 micrograms/kg body weight during concomitantly applied subcutaneous (s.c.) IL-2 treatment. Acute but transient BIS-1 F(ab')2-related toxicity was observed at the 3 and 5 micrograms/kg dose level, and the maximum tolerated dose (MTD) was set at 5 micrograms/kg. A dose-dependent binding of BIS-1 F(ab')2 to circulating T lymphocytes was found. The in vivo occupancy of CD3 molecules on T lymphocytes was highest at teh end of the infusion period and then rapidly decreased, as shown by flow cytometry. A much slower decrease of BIS-1 F(ab')2 binding was observed in vitro, suggesting migration of BIS-1 F(ab')2-loaded T lymphocytes from the circulation. A strong but transitory leukopenia was observed, in which LFA-1 alpha bright, CD3/CD8 double positive T cells left the circulation preferentially. This phenomenon was most likely induced by elevated TNF-alpha and IFN-gamma plasma levels, which were at a maximum shortly after the end of the infusion. Isolated peripheral blood mononuclear cells obtained from patients directly after treatment with BIS-1 F(ab')2 at the 3 and 5 micrograms/kg dose level showed increased EGP-2-directed antitumor activity.
Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results. [2022]Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC).
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]The anti-tumour x anti-T-cell bispecific monoclonal antibody (biMAb) OC/TR is a biologically produced biMAb combining the anti-ovarian carcinoma activity of the MOv18 MAb with anti-CD3/T-cell receptor (TCR) complex activity. In this study, the in vitro binding characteristics of the OC/TR biMAb and its tumour targeting potential in nude mice with Hela tumours was studied. Scatchard analysis revealed that the affinity constant of the biMAb was 7 times lower than the affinity of the parental MOv18 antibody. Uptake of the OC/TR antibody in the Hela xenografts in nude mice was significantly higher than the tumour uptake of an irrelevant control antibody, indicating that the radioiodinated OC/TR biMAb specifically localized in the tumour xenografts. However, tumour uptake was significantly lower than the tumour uptake of the parental MOv18 antibody. This reduced tumour uptake most likely is a result of its reduced affinity. We conclude that, despite the loss of bivalent tumour cell binding, the biMAb OC/TR can still specifically localize in tumours. This indicates that the first prerequisite of an effective therapeutic approach using systemically applied biMAb can be met. Whether the interaction with human T-cells will affect the tumour targeting potential of the biMAb in patients remains to be investigated.
Localization of monoclonal antibody G250 and bispecific monoclonal antibody CD3/G250 in human renal-cell carcinoma xenografts: relative effects of size and affinity. [2019]A study was made of the relative effects of size and binding strength of various forms of the monoclonal antibody (MAb) G250, reacting with primary and metastatic human renal-cell carcinoma (RCC), on the localization in human RCC xenografts in nude mice. Preferential tumor localization was demonstrated after injection of 125I-labelled intact IgG, with increasing tumor/non-tumor ratios in time. Approximately 27.4% of the injected dose/gram (%ID/g) was localized in the xenograft 24 hr post-injection. A control MAb did not preferentially localize in xenografts. With F(ab')2 fragments, higher tumor/blood ratios were obtained, although a lower percentage of injected dose per gram was bound to the tumor, 24 and 48 hr post-injection. Using a bispecific MAb CD3/G250 F(ab')2 fragment, which reacts with CD3 on human T lymphocytes and binds monovalently to RCC, an enhanced accumulation in tumor tissue was also observed. The %ID/g tumor obtained with bispecific CD3/G250 F(ab')2 was comparable with %ID/g tumor found with G250 F(ab')2. The 10-fold lower binding affinity to RCC compared with intact IgG or F(ab')2 had only marginal effects on %ID/g tumor. These results show that MAb G250 preferentially localizes to RCC xenografts. Because injection of F(ab')2 fragments resulted in higher tumor/non-tumor ratios, G250 F(ab')2 may therefore be more suitable for diagnostic evaluation of RCC in patients. The tumor uptake is more dependent on size than on affinity. Furthermore, the data obtained with bispecific MAb CD3/G250 F(ab')2 support the hypothesis that this bispecific MAb may be able to target cytotoxic T lymphocytes to RCC in humans to mediate destruction of RCC.