BGB-53038 for Cancer

Recruiting at19 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: BeiGene

Must not be taking: Anti-RAS treatments

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

No Placebo Group

Trial Summary

What is the purpose of this trial?

This is a first-in-human (FIH), open-label, multicenter, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of BGB-53038 as monotherapy in participants with advanced or metastatic solid tumors harboring KRAS mutations or amplification, as well as when used in combination with tislelizumab (also known as BGB-A317) in participants with nonsquamous non-small cell lung cancer (NSCLC) and used in combination with cetuximab in participants with colorectal cancer (CRC). The study consists of 2 phases: Phase 1a Dose Escalation and Safety Expansion and Phase 1b Dose Expansion.

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.

What data supports the idea that BGB-53038 for Cancer is an effective treatment?

The available research shows that immune checkpoint blockade (ICB) therapy, which includes treatments like BGB-53038, is associated with significantly improved survival in patients with advanced solid tumors compared to those who did not receive ICB therapy. Additionally, patients with certain genetic profiles, such as a high tumor mutation burden (TMB), tend to have better outcomes with ICB treatments. This suggests that BGB-53038 can be effective, especially for patients with specific genetic markers. However, the effectiveness can vary based on individual genetic factors. ^{1 2 3 4 5}

What safety data is available for BGB-53038 (Cetuximab) in cancer treatment?

The provided research does not contain specific safety data for BGB-53038 (Cetuximab) or its related names. The studies focus on other cancer treatments like olaparib, veliparib, and prexasertib, as well as immune checkpoint inhibitors combined with bevacizumab. For safety data on BGB-53038, you may need to consult clinical trial registries or specific studies on Cetuximab. ^{6 7 8 9 10}

Is the drug BGB-53038 a promising treatment for cancer?

Yes, BGB-53038, which is related to the protein 53BP1, shows promise as a cancer treatment. Research indicates that 53BP1 can suppress tumor growth, especially in breast cancer, by helping repair damaged DNA and preventing cancer cells from spreading. This makes it a potential target for new cancer therapies. ^{11 12 13 14 15}

Research Team

Study Director

Principal Investigator

BeiGene

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• BGB-53038 (Small Molecule Inhibitor)
• Cetuximab (Monoclonal Antibodies)
• Tislelizumab (Monoclonal Antibodies)

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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 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]

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]

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]

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]

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]

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]

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]

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 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]

References

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

High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naïve Patients with Diverse Cancers. [2021]

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

Identification of biomarkers of immune checkpoint blockade efficacy in recurrent or refractory solid tumor malignancies. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Pancancer analysis of a potential gene mutation model in the prediction of immunotherapy outcomes. [2022]

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

Blood Tumor Mutational Burden as a Predictive Biomarker in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC). [2021]

5. England 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. [2022]

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

Olaparib: A Novel Therapy for Metastatic Breast Cancer in Patients With a BRCA1/2 Mutation. [2020]

7. United States 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). [2023]

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

Adverse reactions associated with immune checkpoint inhibitors and bevacizumab: A pharmacovigilance analysis. [2023]

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

Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer. [2019]

10. United States 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. [2020]

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

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

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

53BP1 is a haploinsufficient tumor suppressor and protects cells from radiation response in glioma. [2021]

13. England pubmed.ncbi.nlm.nih.gov

53BP1 functions as a tumor suppressor in breast cancer via the inhibition of NF-κB through miR-146a. [2016]

14. England pubmed.ncbi.nlm.nih.gov

Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers. [2018]

15. Greece pubmed.ncbi.nlm.nih.gov

Expression of 53BP1 as a cisplatin-resistant marker in patients with lung adenocarcinomas. [2019]