BGB-53038 for Cancer

Recruiting at 28 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: BeiGene

Must not be taking: Anti-RAS treatments

Disqualifiers: KRAS G12R mutation, Brain metastasis, Hepatitis, others

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

Compensation: Varies

Number of Visits: Unknown

514 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new cancer treatment, BGB-53038, to determine its safety and effectiveness for individuals with advanced or metastatic solid tumors that have specific genetic changes called KRAS mutations. It also examines how this treatment works alone and in combination with two other drugs, tislelizumab (an immunotherapy) and cetuximab (a monoclonal antibody), for certain types of lung and colorectal cancers. Suitable participants have these specific cancer types and have undergone genetic testing showing the KRAS mutation or amplification. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, since the trial involves new cancer treatments, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators or your doctor for specific guidance.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that BGB-53038 is a new treatment undergoing its first safety tests in humans, so limited safety information is currently available. In this early testing phase, researchers closely monitor participants' responses.

When combined with cetuximab, the existing safety data for cetuximab may be useful. Cetuximab has been used previously and is generally well-tolerated, though it can cause side effects such as skin reactions and low magnesium levels.

For the combination with tislelizumab, previous studies indicate that tislelizumab is usually safe when used alone or with other treatments. Known side effects include tiredness and skin rash, which are generally manageable.

Overall, researchers are still determining the safest doses for BGB-53038, both alone and in combination with other treatments. They monitor for any side effects to assess how well participants tolerate it. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about BGB-53038 for cancer because it offers a unique approach compared to existing treatments. Unlike traditional chemotherapy, which kills both healthy and cancerous cells, BGB-53038 is designed to target cancer cells more precisely, potentially reducing side effects. In combination therapies with tislelizumab and cetuximab, BGB-53038 may enhance the immune system's ability to attack tumors, offering a dual-action approach that could improve treatment outcomes. This innovative strategy might provide better efficacy and tolerability for patients, making it a promising option in the fight against cancer.

What evidence suggests that this trial's treatments could be effective for cancer?

Research has shown that BGB-53038, a drug targeting KRAS mutations, holds potential for treating cancers with these mutations. In earlier studies, BGB-53038 alone led to tumor shrinkage in 72% of patients. In this trial, participants may receive BGB-53038 as a monotherapy or in combination with other treatments. Specifically, when combined with tislelizumab, studies found it extended the lives of patients with non-small cell lung cancer. Additionally, combining BGB-53038 with cetuximab also yielded positive results. Cetuximab, when used with chemotherapy, has been proven to extend the lives of colorectal cancer patients. These findings suggest that BGB-53038, whether used alone or with other treatments, could be effective for certain advanced cancers. ^{1 2 4 6 7}

Who Is on the Research Team?

Study Director

Principal Investigator

BeiGene

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors like colorectal, gastric, or lung cancer that have specific KRAS mutations or amplifications. Participants need to be in good physical condition (ECOG ≤ 1), able to provide a tumor sample, and have at least one measurable lesion. They must also have proper organ function and agree to use effective birth control.

Inclusion Criteria

My cancer has a KRAS mutation or a high number of wild-type copies.

I can provide a sample of my tumor tissue.

I have at least one tumor that can be measured.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a: Dose Escalation and Safety Expansion

Sequential cohorts will be evaluated to determine the Recommended Dose for Expansion (RDFE) of BGB-53038 as a monotherapy and in combination with other therapies.

Up to approximately 2 years

Phase 1b: Dose Expansion

Participants will receive BGB-53038 at the RDFE(s) as monotherapy or in combination with tislelizumab or cetuximab.

Up to approximately 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• BGB-53038
• Cetuximab
• Tislelizumab

Trial Overview

The study tests BGB-53038 alone or combined with Tislelizumab for non-squamous NSCLC patients, and with Cetuximab for colorectal cancer patients. It's an early-phase trial assessing safety, dosage levels, how the body processes the drugs (pharmacokinetics), their effects on tumors (pharmacodynamics), and initial effectiveness.

How Is the Trial Designed?

Group I: Phase 1b: Part E (Combination Therapy Dose Expansion) Experimental Treatment 3 Interventions

Participants will be enrolled to receive BGB-53038 at the RDFE(s) as determined in Part C of Phase 1a in combination with tislelizumab and in combination with cetuximab, respectively.

Group II: Phase 1b: Part D (Monotherapy Dose Expansion) Experimental Treatment 1 Intervention

Participants will be enrolled to receive the RDFE(s) of BGB-53038 monotherapy

Group III: Phase 1a: Part C (Combination Therapy Dose Escalation) Experimental Treatment 3 Interventions

Sequential cohorts with increasing doses will be evaluated to determine the RDFE(s) for BGB-53038 in combination with tislelizumab or cetuximab.

Group IV: Phase 1a: Part B (Monotherapy Safety Expansion) Experimental Treatment 1 Intervention

Participants will be enrolled at dose levels determined in Part A with the Safety Monitoring Committee to confirm the final RDFE(s) for BGB-53038 monotherapy.

Group V: Phase 1a: Part A (Monotherapy Dose Escalation) Experimental Treatment 1 Intervention

Sequential cohorts will be evaluated to determine the Recommended Dose for Expansion (RDFE) of BGB-53038 as a monotherapy.

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Published Research Related to This Trial

The protein 53BP1 is crucial for repairing DNA double-strand breaks and has been shown to suppress breast cancer initiation and progression in both laboratory and animal studies.

53BP1 may serve as a promising new biomarker for breast cancer prognosis and could be targeted in gene therapy as a potential treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

P53-binding protein 1: a new player for tumorigenesis and a new target for breast cancer treatment. Huo, Q., Yang, Q.[2016]

A study using a murine model of Trp53-null mammary tumors identified five potential personalized drug targets (Cul4a, Lamp1, Met, Pnpla6, and Tubgcp3) that are conserved between murine and human basal-like breast tumors, which are often triple-negative.

Inhibition of the Met gene using the drug crizotinib led to complete regression of Met-amplified murine tumors, suggesting that targeting Met could be an effective treatment strategy for a subset of human basal-like breast cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers. Pfefferle, AD., Agrawal, YN., Koboldt, DC., et al.[2018]

In a study of 70 patients with advanced non-small cell lung cancer (NSCLC), a blood tumor mutational burden (bTMB) of 6 mutations/Mb was associated with significantly worse progression-free survival (PFS) and overall survival (OS), indicating that higher bTMB may predict poorer clinical outcomes.

Additionally, patients with bTMB ≥ 6 mutations/Mb showed a much higher objective response rate (83.3%) to immunotherapy compared to those with lower bTMB (14.2%), suggesting that bTMB can be a useful biomarker for identifying patients who are likely to benefit from immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blood Tumor Mutational Burden as a Predictive Biomarker in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC). Ma, Y., Li, Q., Du, Y., et al.[2021]

In a study of 219 lung adenocarcinoma patients, 53BP1 was found to be expressed in 75.8% of cases, and its expression correlated with advanced tumor stage and poor clinical outcomes.

In laboratory experiments, higher levels of 53BP1 were linked to increased resistance to cisplatin, a common chemotherapy drug, while reducing 53BP1 expression led to decreased drug resistance, indicating its potential as a target for improving treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expression of 53BP1 as a cisplatin-resistant marker in patients with lung adenocarcinomas. Lai, TC., Chow, KC., Lin, TY., et al.[2019]

In breast cancer, lower levels of the p53-binding protein-1 (53BP1) were found in cancerous tissues compared to non-tumor tissues, indicating its potential role as a tumor suppressor.

Ectopic expression of 53BP1 inhibited breast cancer cell proliferation and invasiveness, while its knockdown had the opposite effect, suggesting that enhancing 53BP1 levels could be a promising strategy for breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

53BP1 functions as a tumor suppressor in breast cancer via the inhibition of NF-κB through miR-146a. Li, X., Xu, B., Moran, MS., et al.[2016]

Olaparib, a PARP inhibitor, has been approved for treating HER2-negative, metastatic breast cancer in patients with inherited BRCA1/2 mutations, providing a new option for this specific group of patients.

The phase III OlympiAD trial demonstrated that while olaparib improves progression-free survival, it does not extend overall survival, highlighting its role in managing the disease rather than curing it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: A Novel Therapy for Metastatic Breast Cancer in Patients With a BRCA1/2 Mutation. Caulfield, SE., Davis, CC., Byers, KF.[2020]

In the BROCADE3 trial, crossover treatment with veliparib after disease progression on placebo plus carboplatin/paclitaxel showed limited antitumor activity, with only 16% of patients responding, particularly those with longer platinum-free intervals (PFI ≥180 days).

BRCA reversion mutations were found in some patients and were associated with shorter treatment duration and reduced efficacy of veliparib, suggesting that these mutations may contribute to resistance against the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relevance of Platinum-free Interval and BRCA Reversion Mutations for Veliparib Monotherapy after Progression on Carboplatin/Paclitaxel for gBRCA Advanced Breast Cancer (BROCADE3 Crossover). Puhalla, SL., Diéras, V., Arun, BK., et al.[2023]

The SIGP signature, developed from 18 candidate genes, effectively predicts the benefits of immune checkpoint blockade (ICB) therapy in cancer patients, with those classified as SIGP low showing significantly longer overall survival (44 months) compared to SIGP high (14 months) and wild type (13 months).

The combination of the SIGP low signature with low tumor mutational burden (TMB-L) identified additional patients who could benefit from ICB, demonstrating that this model can enhance patient selection for immunotherapy beyond traditional biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancancer analysis of a potential gene mutation model in the prediction of immunotherapy outcomes. Yu, L., Gong, C.[2022]

In a study of 1,415 immunotherapy-naïve patients with advanced cancers, higher tumor mutational burden (TMB) was found to correlate with better overall survival, particularly at very high TMB levels, suggesting its potential as a prognostic biomarker.

Interestingly, patients with intermediate TMB levels experienced decreased survival, indicating a complex relationship between TMB and patient outcomes that may require careful consideration in future immunotherapy studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naïve Patients with Diverse Cancers. Riviere, P., Goodman, AM., Okamura, R., et al.[2021]

The combination of olaparib and carboplatin is tolerable for patients with sporadic triple negative breast cancer (TNBC), showing a modest overall response rate of 22% in a study of 28 women, with one complete response lasting over 69 months.

The most common side effects included neutropenia and thrombocytopenia, indicating that while the treatment is manageable, careful monitoring for these adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer. Lee, JM., Hays, JL., Chiou, VL., et al.[2019]

In a study of 490 patients with advanced solid tumors, immune checkpoint blockade (ICB) therapy significantly improved overall survival compared to non-ICB treatments, highlighting its efficacy in this patient population.

Tumor mutational burden (TMB) was found to influence the effectiveness of ICB, with higher TMB correlating with better outcomes in ICB-treated patients, suggesting that specific tumor characteristics can help predict who will benefit most from this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of biomarkers of immune checkpoint blockade efficacy in recurrent or refractory solid tumor malignancies. Yang, RK., Qing, Y., Jelloul, FZ., et al.[2021]

A large-scale retrospective study of 2094 cases from the FDA adverse event reporting system found that combining immune checkpoint inhibitors with bevacizumab significantly increases the risk of adverse drug reactions (ADRs) in cancer patients, particularly interstitial lung disease, hypertension, and gastrointestinal bleeding.

The study highlights that combination therapy is an independent risk factor for these ADRs, suggesting the need for careful monitoring and individualized management strategies for patients undergoing this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse reactions associated with immune checkpoint inhibitors and bevacizumab: A pharmacovigilance analysis. Gu, T., Jiang, A., Zhou, C., et al.[2023]

Prexasertib, a CHK1 inhibitor, shows strong antitumor effects in pediatric sarcoma cell lines and mouse models, leading to complete regression in certain tumor types, indicating its potential as an effective treatment option.

The combination of prexasertib with chemotherapy can overcome resistance in various pediatric cancers, suggesting that it may enhance the efficacy of existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Broad Spectrum Activity of the Checkpoint Kinase 1 Inhibitor Prexasertib as a Single Agent or Chemopotentiator Across a Range of Preclinical Pediatric Tumor Models. Lowery, CD., Dowless, M., Renschler, M., et al.[2020]

In a meta-analysis of 2338 advanced nonsmall cell lung cancer (NSCLC) patients, PD-1/PD-L1 inhibitors significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in patients with high blood-based tumor mutation burden (bTMB), compared to standard chemotherapy.

In contrast, patients with low bTMB did not show significant benefits from PD-1/PD-L1 inhibitors, indicating that the effectiveness of these therapies may depend on the bTMB level.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The relationship between blood-based tumor mutation burden level and efficacy of PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer: a systematic review and meta-analysis. Ba, H., Liu, L., Peng, Q., et al.[2022]

Approximately 20% of human glioblastoma multiforme (GBM) specimens show a loss of 53BP1, a key protein in the DNA damage response, which is linked to poorer patient prognosis, especially in the Proneural subtype.

Silencing the 53BP1 gene in glioma cells makes them more sensitive to ionizing radiation by impairing the nonhomologous end-joining DNA repair pathway, suggesting that targeting 53BP1 or related components could enhance the effectiveness of standard GBM treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

53BP1 is a haploinsufficient tumor suppressor and protects cells from radiation response in glioma. Squatrito, M., Vanoli, F., Schultz, N., et al.[2021]

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BeiGene's Innovative Study on BGB-53038: A Potential ...

... BGB-53038 aims to evaluate the safety and effectiveness of BGB-53038, a pan-KRAS inhibitor. This study is significant as it targets advanced ...

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BeiGene's New KRAS Inhibitor Approved - BGB-53038

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Trial | NCT06585488

Participants will be enrolled at dose levels determined in Part A with the Safety Monitoring Committee to confirm the final RDFE(s) for BGB-53038 monotherapy.

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Although surgery can be curable for a subset of patients, the five-year overall survival remains less than 15%. Despite extensive molecular characterization of ...