BGB-53038 for Cancer
Recruiting in Palo Alto (17 mi)
+19 other 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.12345
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.678910
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.1112131415
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.
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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 OverviewThe 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
5Treatment groups
Experimental Treatment
Group I: Phase 1b: Part E (Combination Therapy Dose Expansion)Experimental Treatment3 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 Treatment1 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 Treatment3 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 Treatment1 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 Treatment1 Intervention
Sequential cohorts will be evaluated to determine the Recommended Dose for Expansion (RDFE) of BGB-53038 as a monotherapy.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Usc Norris Comprehensive Cancer Center (Nccc)Los Angeles, CA
University of Kansas Medical Center Research InstituteKansas City, KS
The University of Texas Md Anderson Cancer CenterHouston, TX
Sidney Kimmel Comprehensive Cancer At Johns HopkinsBaltimore, MD
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Who Is Running the Clinical Trial?
BeiGeneLead Sponsor
References
High Tumor Mutational Burden Correlates with Longer Survival in Immunotherapy-Naïve Patients with Diverse Cancers. [2021]Higher tumor mutational burden (TMB) has been correlated with response to checkpoint blockade immunotherapy. However, it is unclear whether TMB independently serves as a prognostic biomarker for outcomes in immunotherapy-naïve patients. Here, we evaluated the relationship between TMB and overall survival in 1,415 immunotherapy-naïve patients with diverse advanced malignancies. TMB was studied both as a tiered variable (low ≤5 mutations/Mb, intermediate >5 and <20, high ≥20 and <50, and very high ≥50) and as a continuous variable. Interestingly, we observed a parabolic correlation between TMB and overall survival, in which intermediate-range TMB correlated with decreased survival, whereas low and very high TMB correlated with improved outcomes (median survival: 238, 174, 195, and 350 weeks for low, intermediate, high, and very high TMB, respectively; multivariate P < 0.01). This corresponded to an HR of 1.29 (95% confidence interval, 1.07-1.54; P < 0.01) for intermediate-range TMB on multivariable survival analysis correcting for known confounders, including primary tumor of origin. These results demonstrate that TMB may have utility as a prognostic biomarker in immunotherapy-naïve patients, with a protective effect at higher TMBs, and that studies of survival in immunotherapy-treated patients may need to stratify or randomize by TMB in a nonlinear fashion to account for this confounding.
Identification of biomarkers of immune checkpoint blockade efficacy in recurrent or refractory solid tumor malignancies. [2021]Patients with advanced solid malignancies recurrent or resistant to standard therapy have limited treatment options. The role of molecular biomarkers for predicting immune checkpoint blockade (ICB) efficacy are not well characterized in these patients. Tumor mutational profiles of 490 patients with a variety of advanced solid tumors enrolled in a prospective protocol were analyzed to identify prognostic and predictive biomarkers. ICB therapy was defined as treatment with any CTLA-4, PD-1, and/or PD-L1 monoclonal antibody. ICB treatment was associated with significantly improved overall survival compared to non-ICB therapy. Multivariate regression analysis including the two variables of tumor mutation burden (TMB) and ICB, and their interaction term, showed favorable survival associated with ICB, unfavorable survival associated with TMB without ICB treatment, and improved outcome with increasing TMB in ICB treated patients. Tumor TP53 mutation was associated with worse survival, but these patients still benefitted from ICB. A more comprehensive multivariate analysis including cancer type, specific gene mutations, and TMB revealed that ICB treatment was an independent predictor of improved overall survival. Therefore, ICB-based therapeutic trials are beneficial in patients with advanced solid malignancies, but the most benefit may be restricted to patients with the right combination of TMB and specific tumor histology and genotype.
Pancancer analysis of a potential gene mutation model in the prediction of immunotherapy outcomes. [2022]Background: Immune checkpoint blockade (ICB) represents a promising treatment for cancer, but predictive biomarkers are needed. We aimed to develop a cost-effective signature to predict immunotherapy benefits across cancers. Methods: We proposed a study framework to construct the signature. Specifically, we built a multivariate Cox proportional hazards regression model with LASSO using 80% of an ICB-treated cohort (n = 1661) from MSKCC. The desired signature named SIGP was the risk score of the model and was validated in the remaining 20% of patients and an external ICB-treated cohort (n = 249) from DFCI. Results: SIGP was based on 18 candidate genes (NOTCH3, CREBBP, RNF43, PTPRD, FAM46C, SETD2, PTPRT, TERT, TET1, ROS1, NTRK3, PAK7, BRAF, LATS1, IL7R, VHL, TP53, and STK11), and we classified patients into SIGP high (SIGP-H), SIGP low (SIGP-L) and SIGP wild type (SIGP-WT) groups according to the SIGP score. A multicohort validation demonstrated that patients in SIGP-L had significantly longer overall survival (OS) in the context of ICB therapy than those in SIGP-WT and SIGP-H (44.00 months versus 13.00 months and 14.00 months, p < 0.001 in the test set). The survival of patients grouped by SIGP in non-ICB-treated cohorts was different, and SIGP-WT performed better than the other groups. In addition, SIGP-L + TMB-L (approximately 15% of patients) had similar survivals to TMB-H, and patients with both SIGP-L and TMB-H had better survival. Further analysis on tumor-infiltrating lymphocytes demonstrated that the SIGP-L group had significantly increased abundances of CD8+ T cells. Conclusion: Our proposed model of the SIGP signature based on 18-gene mutations has good predictive value for the clinical benefit of ICB in pancancer patients. Additional patients without TMB-H were identified by SIGP as potential candidates for ICB, and the combination of both signatures showed better performance than the single signature.
Blood Tumor Mutational Burden as a Predictive Biomarker in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC). [2021]This study was designed to investigate the impact of blood tumor mutational burden (bTMB) on advanced NSCLC in Southwest China. The relationship between the tTMB estimated by next-generation sequencing (NGS) and clinical outcome was retrospectively analyzed in tissue specimens from 21 patients with advanced NSCLC. Furthermore, the relationship between the bTMB estimated by NGS and clinical outcome was retrospectively assessed in blood specimens from 70 patients with advanced NSCLC. Finally, 13 advanced NSCLC patients were used to evaluate the utility of bTMB assessed by NGS in differentiating patients who would benefit from immunotherapy. In the tTMB group, tTMB ≥ 10 mutations/Mb was related to inferior progression-free survival (PFS) (hazard ratio [HR], 0.30; 95% CI, 0.08-1.17; log-rank P = 0.03) and overall survival (OS) (HR, 0.30; 95% CI, 0.08-1.16; log-rank P = 0.03). In the bTMB group, bTMB ≥ 6 mutations/Mb was associated with inferior PFS (HR, 0.32; 95% CI, 0.14-1.35; log-rank P < 0.01) and OS (HR, 0.31; 95% CI, 0.14-0.7; log-rank P < 0.01). In the immunotherapy section, bTMB ≥ 6 mutations/Mb was related to superior PFS (HR, 0.32; 95% CI, 0.14-1.35; log-rank P < 0.01) and objective response rates (ORRs) (bTMB < 6: 14.2%; 95% CI, 0.03-1.19; bTMB ≥ 6: 83.3%; 95% CI, 0.91-37.08; P = 0.02). These findings suggest that bTMB is a validated predictive biomarker for determining the clinical outcome of advanced NSCLC patients and may serve as a feasible predictor of the clinical benefit of immunotherapies (anti-PD-1 antibody) in the advanced NSCLC population in Yunnan Province.
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]The predictive role of blood-based tumor mutation burden (bTMB) for selecting advanced nonsmall cell lung cancer (NSCLC) patients who might benefit from immune checkpoint inhibitors (ICIs) is still under debate. Therefore, the purpose of this meta-analysis was to evaluate the efficacy of programmed cell death 1 (PD-1) /programmed cell death ligand 1 (PD-L1) inhibitors versus that of standard-of-care therapy in patients with NSCLC who were bTMB high and bTMB low.
Olaparib: A Novel Therapy for Metastatic Breast Cancer in Patients With a BRCA1/2 Mutation. [2020]Breast cancer is the most frequently diagnosed cancer in women globally. Genetic mutations can increase the risk of developing breast cancer. Inherited germline mutations in BRCA1 and BRCA2 tumor suppressor genes (gBRCAm) account for 5% to 10% of breast cancer cases. The recent approval of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in HER2-negative, metastatic breast cancer provides an additional treatment option for patients with a gBRCAm. Inhibition of PARP results in the trapping of the PARP-DNA complex at replication forks, causing single-strand breaks to become double-strand breaks (DSBs). PARP trapping and the accumulation of DSBs ultimately leads to cell apoptosis. Cells deficient in BRCA1/2 are particularly sensitive to the effects of PARP inhibition, as cells lacking these functional proteins are unable to repair DSBs, resulting in synthetic lethality. The phase III OlympiAD trial showed a progression-free survival benefit but no overall survival benefit, leading to the US Food and Drug Administration approval of olaparib. The purpose of this article is to describe current data regarding the use of olaparib in metastatic breast cancer, its role in the treatment of patients with a gBRCAm, and the clinical implications of its approval for oncology advanced practitioners.
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]Label="PURPOSE">Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (gBRCA)-associated breast cancer enrolled in the BROCADE3 trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel.
Adverse reactions associated with immune checkpoint inhibitors and bevacizumab: A pharmacovigilance analysis. [2023]Immune checkpoint inhibitors (ICIs) combined with the anti-angiogenesis drug bevacizumab is one of the future directions of immunotherapy. However, the potential adverse drug reactions (ADRs) caused by combination therapy remain unclear. Current research on ADRs of combination therapy in cancer patients is extremely limited. Our study aims to help determine the safety of combination therapy. We downloaded the ADR reports on combination therapy, from the first quarter of 2012 to the fourth quarter of 2021, from the FDA adverse event reporting system (FAERS) database and conducted a large-scale retrospective study. The ADR signals were monitored by reporting odds ratio (ROR) and analyzing the risk of different ADRs in patients with Pan-cancer. A total of 2094 cases were selected, after excluding duplicate data and the use of chemotherapy drugs. We evaluated the risk of ADR in Pan-cancer patients. Combination therapy was an independent risk factor for adverse drug reactions associated with interstitial lung disease (OR: 8.62; 95% CI: 6.14-12.10, P
Phase I/Ib study of olaparib and carboplatin in women with triple negative breast cancer. [2019]Label="PURPOSE" NlmCategory="OBJECTIVE">To investigate the safety, activity, and potential biomarkers of response to olaparib and carboplatin combination in sporadic triple negative breast cancer (TNBC). EXPERIMENTAL DESIGN: Metastatic or recurrent TNBC patients with no germline BRCA mutation or with BRCAPro scores <10% and a negative family history were eligible. A 3+3 dose escalation tested olaparib capsules (400mg bid, days1-7) with carboplatin AUC3-5 on day1 or 2 every 21 days, ≤ 8 cycles, with olaparib 400mg bid maintenance. Peripheral blood mononuclear cells were collected for polymorphisms and PAR levels, and paired tumor biopsies (pre-/post-cycle 1) for proteomics and apoptosis endpoints.
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]Checkpoint kinase 1 (CHK1) inhibitors potentiate the DNA-damaging effects of cytotoxic therapies and/or promote elevated levels of replication stress, leading to tumor cell death. Prexasertib (LY2606368) is a CHK1 small-molecule inhibitor under clinical evaluation in multiple adult and pediatric cancers. In this study, prexasertib was tested in a large panel of preclinical models of pediatric solid malignancies alone or in combination with chemotherapy.
P53-binding protein 1: a new player for tumorigenesis and a new target for breast cancer treatment. [2016]Breast cancer remains the most common and fatal cancer in women and has been recognized as a genetic disease. Recently, accumulating evidences have showed that p53-binding protein 1 (53BP1) plays an important role in DNA double-strand breaks (DSBs) repair induced by radiation. In vitro experiments have indicated its interaction with many other genes or proteins for tumor suppression or tumorigenesis via pathways associated with DNA repair, cell-cycle control, apoptosis and cell senescence. In vivo studies also showed suppressive effect of 53BP1 on tumor initiation and progression. Therefore, we hypothesize that 53BP1 has a profound effect on suppressing breast cancer as a tumor suppressor and will be an important new biomarker for breast cancer prognosis. Furthermore, 53BP1 gene therapy will be a potential therapeutic strategy for breast cancer.
53BP1 is a haploinsufficient tumor suppressor and protects cells from radiation response in glioma. [2021]The DNA damage response (DDR) plays a crucial role in tumor development in different tissues. Here, we show that p53-binding protein 1 (53BP1), a key element of the DDR, is heterozygously lost in approximately 20% of human glioblastoma multiforme (GBM) specimens, primarily of the Proneural subtype, and low 53BP1 expression levels are associated with worse prognosis. We present evidence that 53BP1 behaves as haploinsufficient tumor suppressor in a mouse model of platelet-derived growth factor-induced gliomagenesis. We also show that very low level of 53BP1 as found in 53BP1 null gliomas or robust 53BP1 gene silencing in glioma cell lines (but not 53BP1 heterozygous tumors or partial gene knockdown) sensitizes glioma cells to ionizing radiation (IR), both in vitro and in vivo. We further show the 53BP1 gene silencing induces defects in the nonhomologous end-joining (NHEJ) DNA repair pathway. These deficiencies lead to a failure to fully repair the damaged DNA upon exposure of glioma cells to IR with a consequent prolonged cell-cycle arrest and increased apoptosis. Our data suggest that either 53BP1 or other NHEJ components may be critical molecules to be pharmacologically targeted in GBM in combination with standard therapies.
53BP1 functions as a tumor suppressor in breast cancer via the inhibition of NF-κB through miR-146a. [2016]p53-binding protein-1 (53BP1) plays a critical role in cell cycle checkpoint and DNA repair activities. Recently, 53BP1 was recognized as a potential tumor suppressor gene. In this study, we investigated its tumor suppressor function in breast cancer. In clinical samples, we observed a lower level of 53BP1 expression in the cancer lesions than in the matched non-tumor tissues. Furthermore, the 53BP1 level showed a gradual decrease during the progression from precancerous to cancer lesion. Ectopic expression of 53BP1 can significantly inhibit cell proliferation and curb the invasiveness in breast cancer cell lines, whereas knockdown of 53BP1 by RNA interference had the opposite effects. Additionally, 53BP1 markedly inhibited xenograft formation and metastasis of breast cancer cells in nude mice. Both in vitro and in vivo studies revealed that the 53BP1 expression level was inversely correlated to the function of nuclear factor-kappaB (NF-κB), which contributes to the invasion and metastasis of breast cancer. Importantly, the inhibitory effect of 53BP1 on NF-κB activity was shown to be mediated by the upregulation of miR-146a. Together, our findings demonstrated that 53BP1 has a potent tumor suppressor activity in breast cancer, and it may serve as a novel target for breast cancer prevention and treatment.
Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers. [2018]Targeted therapies against basal-like breast tumors, which are typically 'triple-negative breast cancers (TNBCs)', remain an important unmet clinical need. Somatic TP53 mutations are the most common genetic event in basal-like breast tumors and TNBC. To identify additional drivers and possible drug targets of this subtype, a comparative study between human and murine tumors was performed by utilizing a murine Trp53-null mammary transplant tumor model. We show that two subsets of murine Trp53-null mammary transplant tumors resemble aspects of the human basal-like subtype. DNA-microarray, whole-genome and exome-based sequencing approaches were used to interrogate the secondary genetic aberrations of these tumors, which were then compared to human basal-like tumors to identify conserved somatic genetic features. DNA copy-number variation produced the largest number of conserved candidate personalized drug targets. These candidates were filtered using a DNA-RNA Pearson correlation cut-off and a requirement that the gene was deemed essential in at least 5% of human breast cancer cell lines from an RNA-mediated interference screen database. Five potential personalized drug target genes, which were spontaneously amplified loci in both murine and human basal-like tumors, were identified: Cul4a, Lamp1, Met, Pnpla6 and Tubgcp3 As a proof of concept, inhibition of Met using crizotinib caused Met-amplified murine tumors to initially undergo complete regression. This study identifies Met as a promising drug target in a subset of murine Trp53-null tumors, thus identifying a potential shared driver with a subset of human basal-like breast cancers. Our results also highlight the importance of comparative genomic studies for discovering personalized drug targets and for providing a preclinical model for further investigations of key tumor signaling pathways.
Expression of 53BP1 as a cisplatin-resistant marker in patients with lung adenocarcinomas. [2019]DNA repair is one of the major causes of spontaneous drug and radiation resistance in patients with lung adenocarcinomas (LADC). 53BP1 is a mediator that relays signals from DNA damage sensors and activates various effectors for the DNA repair and cell survival. In this study we investigated the clinical and biological significance of 53BP1. Expression of 53BP1 was detected by immunoblotting and immunohistochemistry. Our data showed that 53BP1 was detected in 166 (75.8%) of 219 LADC patients. Expression of 53BP1 correlated with tumor stage, cigarette smoking, lymphovascular invasion and poor clinical outcome. In vitro, increased 53BP1 expression elevated drug resistance, and silencing of 53BP1 expression reduced cisplatin resistance. Our results suggest that 53BP1 expression plays an important role in cisplatin resistance and predicts the prognosis for LADC.