BG-C477 for Cancer

Recruiting at 12 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: BeiGene

Must not be taking: CEA-targeted ADCs, TOP1 inhibitors

Disqualifiers: Severe allergies, Brain metastasis, others

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

Compensation: Varies

Number of Visits: Unknown

21 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of BG-C477 alone and in combination with anticancer agents in participants with selected advanced solid tumors.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug BG-C477 for cancer?

Research shows that carcinoembryonic antigen (CEA) levels can help predict how well certain cancer treatments work. For example, in metastatic colorectal cancer, lower baseline CEA levels were linked to better responses to bevacizumab-based therapy, suggesting that monitoring CEA could be useful in assessing treatment effectiveness. ^{1 2 3 4 5}

What safety data exists for BG-C477 or related treatments?

A study on a vindesine-anti-CEA conjugate, which may be related to BG-C477, showed no obvious toxicity or allergic reactions in patients with advanced cancer, even at higher doses. ^{6 7 8 9 10}

How is the drug BG-C477 unique in treating cancer?

BG-C477 is an antibody-drug conjugate (ADC) that targets a specific protein called CEACAM5, which is overexpressed in many cancers but not in normal tissues. This allows it to deliver a potent cancer-killing agent directly to the tumor, potentially reducing side effects compared to traditional chemotherapy. ^{10 11 12 13 14}

Research Team

Study Director

Principal Investigator

BeiGene

Eligibility Criteria

This trial is for adults with advanced solid tumors that have grown or spread after at least two standard treatments, or when no standard treatment exists. They must be able to perform daily activities with minimal assistance (ECOG ≤1), agree to use effective birth control, and provide a tumor tissue sample. Participants need functioning major organs.

Inclusion Criteria

I agree to provide a sample of my tumor tissue.

I can sign and understand the consent form for the trial.

* Phase 1a (Dose Escalation); Histologically or cytologically confirmed advanced, metastatic, or unresectable solid tumors, who were previously treated with at least 2 lines of standard systemic therapy or for whom no standard treatment is available in the medical judgment of the investigator * ≥ 1 measurable lesion as assessed by RECIST v1.1

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a: BG-C477 Monotherapy Dose Escalation

Sequential cohorts of increasing dose levels of BG-C477 will be evaluated as monotherapy

Approximately 1 year

Phase 1a: BG-C477 Monotherapy Safety Expansion

Selected dose levels that have been determined to be safe in Phase 1a dose escalation will be further evaluated in monotherapy

Approximately 1 year

Phase 1b Part A: BG-C477 Monotherapy Dose Optimization

Participants with selected advanced solid tumors will be evaluated at different dose levels of RDFEs identified in Phase 1a

Approximately 2 years

Phase 1b Part B: Combination Therapy Expansion

Sequential cohorts of increasing dose levels of BG-C477 will be evaluated in combination with chemotherapy

Approximately 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• BG-C477
• Chemotherapy

Trial Overview The study tests BG-C477's safety and effectiveness alone and combined with chemotherapy in treating solid tumors. It will assess how the body processes the drug, its impact on the body, and its ability to shrink tumors.

Participant Groups

Group I: Phase 1b Part B: Combination Therapy Expansion Experimental Treatment 2 Interventions

Sequential cohorts of increasing dose levels of BG-C477 will be evaluated in combination with chemotherapy.

Group II: Phase 1b Part A: BG-C477 Monotherapy Dose Optimization Experimental Treatment 1 Intervention

Participants with selected advanced solid tumors will be evaluated at different dose levels of RDFEs identified in Phase 1a.

Group III: Phase 1a: BG-C477 Monotherapy Safety Expansion Experimental Treatment 1 Intervention

Selected dose levels that have been determined to be safe in Phase 1a dose escalation will be further evaluated in monotherapy.

Group IV: Phase 1a: BG-C477 Monotherapy Dose Escalation Experimental Treatment 1 Intervention

Sequential cohorts of increasing dose levels of BG-C477 will be evaluated as monotherapy.

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Findings from Research

The novel anti-CEA monoclonal antibody (MAb) R4 effectively targets human colon carcinoma cells and mediates antibody-dependent cell-mediated cytotoxicity (ADCC), showing promise for cancer treatment.

MAb R4 specifically reacts with cancerous tissues while showing no reactivity with normal tissues, indicating its potential as a diagnostic and therapeutic tool for various carcinomas, including colon, breast, and lung cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell mediated cytotoxicity of human colon carcinoma cells by a monoclonal antibody (R4) recognizing the carcinoembryonic antigen (CEA) and CEA-related molecules. Bei, R., Moretti, A., Visco, V., et al.[2019]

In a study of 298 patients with metastatic colorectal cancer (mCRC), lower baseline carcinoembryonic antigen (CEA) serum levels were associated with better responses to bevacizumab-based therapy, showing a disease control rate of 84% in patients with CEA levels below the median compared to 60% in those above.

Patients with lower baseline CEA levels also experienced longer progression-free survival (PFS) and overall survival, with a median PFS benefit of 2.1 months and overall survival of 37.5 months versus 21.4 months for those with higher levels, indicating that CEA levels could be a useful predictor for treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baseline carcinoembryonic antigen (CEA) serum levels predict bevacizumab-based treatment response in metastatic colorectal cancer. Prager, GW., Braemswig, KH., Martel, A., et al.[2022]

In a study of 462 patients with low-risk stage IIA colon cancer, those with elevated perioperative serum CEA levels had a higher recurrence rate (15.9%) compared to those with lower levels, indicating that high CEA levels may signify a worse prognosis.

The findings suggest that patients with high CEA levels should be considered at higher risk and may benefit from adjuvant chemotherapy, as they showed significantly higher mortality and recurrence rates compared to those with lower CEA levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of perioperative serum carcinoembryonic antigen level and recurrence in low-risk stage IIA colon cancer. Kim, HG., Yang, SY., Han, YD., et al.[2021]

In a study of 266 breast cancer patients (87 with stage III and 179 with stage IV), changes in serum carcinoembryonic antigen (CEA) levels were strongly correlated with clinical response to systemic endocrine treatment, particularly in stage IV patients.

Over 50% of stage IV patients had CEA levels exceeding 6 ng/ml at the start or during the first six months of treatment, indicating that elevated CEA could be a significant marker for monitoring treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of serum carcinoembryonic antigen to assess therapeutic response in locally advanced and metastatic breast cancer: a prospective study with external review. Williams, MR., Turkes, A., Pearson, D., et al.[2013]

The study demonstrated that a new fluorescently labeled chimeric anti-CEA antibody significantly improved the detection of colon cancer, providing a brighter fluorescence signal in tumor tissues compared to traditional mouse antibodies.

Fluorescence-guided surgery (FGS) using the chimeric antibody increased the complete resection rate (R0) of tumors from 86% to 96%, indicating its potential for more effective surgical outcomes in colon cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluorescently labeled chimeric anti-CEA antibody improves detection and resection of human colon cancer in a patient-derived orthotopic xenograft (PDOX) nude mouse model. Metildi, CA., Kaushal, S., Luiken, GA., et al.[2021]

In a murine model of colon cancer, combining Ad-CEA vaccination with anti-PD-1 antibody significantly enhanced anti-tumor activity compared to using either treatment alone.

The combination therapy not only increased T-cell infiltration into tumors but also reduced regulatory T cells (Tregs), suggesting a more robust immune response against the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of synchronized anti-PD-1 with Ad-CEA vaccination on inhibition of colon cancer growth. Sun, Y., Wang, S., Yang, H., et al.[2020]

The study involved 8 patients with advanced metastatic carcinoma (4 colorectal and 4 ovarian) who received a radiolabelled vindesine (VDS)-anti-CEA conjugate, demonstrating that the conjugate could localize in 5 out of 8 patients after administration.

No significant toxicity or hypersensitivity reactions were observed from the radiolocalisation or the escalating doses of the conjugate, indicating that it is safe for use in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Localisation and toxicity study of a vindesine-anti-CEA conjugate in patients with advanced cancer. Ford, CH., Newman, CE., Johnson, JR., et al.[2019]

The monoclonal anti-CEA antibody A5B7, when conjugated to CPG2, effectively targets LS174T xenografts, reaching peak concentration within 24 hours, but requires a delay of 5-6 days for prodrug injection to avoid toxicity due to residual enzyme activity in plasma.

A novel three-phase system using the galactosylated anti-CPG2 antibody SB43gal allows for prodrug administration within 24 hours after conjugate injection, resulting in a significant growth delay of the tumor after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody directed enzyme prodrug therapy (ADEPT): a three phase system. Sharma, SK., Bagshawe, KD., Springer, CJ., et al.[2006]

In a study of 23 patients with advanced HER2-expressing solid tumors, RC48-antibody-drug conjugate (ADC) demonstrated a promising objective response rate (ORR) of 43.5% and a median progression-free survival (PFS) of 6.0 months, indicating its potential effectiveness in this patient population.

The treatment was generally well-tolerated, with manageable adverse events such as anemia and leukopenia, and no Grade 4 adverse reactions or deaths reported, suggesting a favorable safety profile for RC48-ADC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RC48-ADC treatment for patients with HER2-expressing locally advanced or metastatic solid tumors: a real-world study. Wang, P., Xia, L.[2023]

The anti-CEA antibody C2-45 was successfully converted from IgG4 to IgG1, enhancing its biological activity for potential cancer treatment.

The new C2-45 (IgG1) variant maintained its ability to bind to the target antigen and effectively induced cytotoxic effects against CEA-expressing tumor cells, making it a promising candidate for immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Replacement of the constant region gene of a novel anti-CEA antibody and characterization of its biological activity]. Huang, J., Shibaguchi, H., Masahide, K.[2006]

Antibody-drug conjugates (ADCs) have significantly advanced breast cancer treatment, with three ADCs currently approved by the FDA, enhancing therapeutic options for patients with both advanced and early-stage breast cancer.

Recent phase 3 trials (ASCENT, TULIP, and DESTINY-Breast03) demonstrated promising efficacy for newer ADCs like sacituzumab govitecan and trastuzumab deruxtecan, indicating their potential to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New antibody-drug conjugates (ADCs) in breast cancer-an overview of ADCs recently approved and in later stages of development. Koster, KL., Huober, J., Joerger, M.[2022]

The study developed a fully human single-domain antibody (UdAb) targeting CEACAM5, which is overexpressed in various cancers, and demonstrated its potential as an effective delivery system for the cytotoxic agent monomethyl auristatin E (MMAE).

The UdAb-MMAE conjugate showed strong antitumor efficacy in multiple cancer cell lines and significantly inhibited tumor growth in mouse models without causing significant weight loss, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel human single-domain antibody-drug conjugate targeting CEACAM5 exhibits potent in vitro and in vivo antitumor activity. Zhu, XY., Li, QX., Kong, Y., et al.[2023]

The novel antibody-drug conjugate platform, Dolasynthen (DS), allows for precise optimization of drug-to-antibody ratios and site-specific conjugation, enhancing targeted drug delivery to tumors.

XMT-1660, an ADC developed using this platform targeting the B7-H4 protein, showed complete tumor regressions in various cancer models and has entered clinical development, indicating promising efficacy in treating cancers with high B7-H4 expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody-Drug Conjugate for the Treatment of Cancer. Toader, D., Fessler, SP., Collins, SD., et al.[2023]

CLDN6-23-ADC is a novel antibody-drug conjugate that selectively targets the CLDN6 protein, which is highly expressed in ovarian and endometrial cancers but not in normal adult tissues, making it a promising therapeutic option.

In preclinical studies, CLDN6-23-ADC demonstrated significant antitumor efficacy, leading to robust tumor regressions and improved survival in mouse models of CLDN6-positive cancers, and it is currently being evaluated in a phase I clinical trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Efficacy of the Antibody-Drug Conjugate CLDN6-23-ADC for the Treatment of CLDN6-Positive Solid Tumors. McDermott, MSJ., O'Brien, NA., Hoffstrom, B., et al.[2023]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Cell mediated cytotoxicity of human colon carcinoma cells by a monoclonal antibody (R4) recognizing the carcinoembryonic antigen (CEA) and CEA-related molecules. [2019]

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

Baseline carcinoembryonic antigen (CEA) serum levels predict bevacizumab-based treatment response in metastatic colorectal cancer. [2022]

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

Association of perioperative serum carcinoembryonic antigen level and recurrence in low-risk stage IIA colon cancer. [2021]

4. England pubmed.ncbi.nlm.nih.gov

The use of serum carcinoembryonic antigen to assess therapeutic response in locally advanced and metastatic breast cancer: a prospective study with external review. [2013]

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

Fluorescently labeled chimeric anti-CEA antibody improves detection and resection of human colon cancer in a patient-derived orthotopic xenograft (PDOX) nude mouse model. [2021]

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

Impact of synchronized anti-PD-1 with Ad-CEA vaccination on inhibition of colon cancer growth. [2020]

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

Localisation and toxicity study of a vindesine-anti-CEA conjugate in patients with advanced cancer. [2019]

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

Antibody directed enzyme prodrug therapy (ADEPT): a three phase system. [2006]

9. England pubmed.ncbi.nlm.nih.gov

RC48-ADC treatment for patients with HER2-expressing locally advanced or metastatic solid tumors: a real-world study. [2023]

10. China pubmed.ncbi.nlm.nih.gov

[Replacement of the constant region gene of a novel anti-CEA antibody and characterization of its biological activity]. [2006]

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

New antibody-drug conjugates (ADCs) in breast cancer-an overview of ADCs recently approved and in later stages of development. [2022]

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

A novel human single-domain antibody-drug conjugate targeting CEACAM5 exhibits potent in vitro and in vivo antitumor activity. [2023]

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

Discovery and Preclinical Characterization of XMT-1660, an Optimized B7-H4-Targeted Antibody-Drug Conjugate for the Treatment of Cancer. [2023]

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

Preclinical Efficacy of the Antibody-Drug Conjugate CLDN6-23-ADC for the Treatment of CLDN6-Positive Solid Tumors. [2023]