JAB-21822 + Cetuximab for Solid Tumors
Recruiting in Palo Alto (17 mi)
+3 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Jacobio Pharmaceuticals Co., Ltd.
Disqualifiers: Brain metastases, Active infection, HBV, HCV, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?This trial is testing a new drug, JAB-21822, alone and with cetuximab in adults with advanced cancers that have a specific genetic change called KRAS G12C. The goal is to see if these treatments are safe and can stop the cancer from growing. Adagrasib is a related molecule that also has FDA approval for patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.
Do I need to stop my current medications for the trial?
The trial protocol does not specify if you need to stop your current medications. However, since the trial involves new treatments, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators for specific guidance.
What data supports the idea that JAB-21822 + Cetuximab for Solid Tumors is an effective treatment?
The available research shows that combining cetuximab with other drugs can improve its effectiveness in treating certain types of cancer. For example, in a study involving KRAS G12C-positive colorectal cancer, a combination of divarasib (a KRAS G12C inhibitor) and cetuximab showed promising results. The study reported a 62.5% response rate in patients who had not previously received KRAS G12C inhibitors, with the response lasting about 6.9 months on average. This suggests that combining cetuximab with other drugs can enhance its effectiveness, especially in cases where cetuximab alone might not be as effective.
12345What safety data is available for JAB-21822 and Cetuximab treatment?
The safety profile of the combination of divarasib (a KRAS G12C inhibitor) and cetuximab was evaluated in a phase 1b trial for KRAS G12C-positive colorectal cancer. The safety profile was consistent with those of the single agents, divarasib and cetuximab. Treatment-related adverse events led to dose reductions in 13.8% of patients, but no treatment withdrawals were reported. This suggests a manageable safety profile for the combination treatment.
36789Is the drug JAB-21822 a promising treatment when used with Cetuximab for solid tumors?
Cetuximab is a drug that targets a protein called EGFR, which is often found in high amounts in certain cancers like lung and colorectal cancer. It has been effective in treating these cancers, especially when other treatments have failed. When combined with JAB-21822, which is also known as Glecirasib, it could potentially enhance the treatment of solid tumors by using Cetuximab's ability to target cancer cells. This combination might offer a promising new approach to treating these types of cancers.
610111213Eligibility Criteria
Adults with advanced solid tumors that have a specific mutation called KRAS G12C can join this trial. They must have tried at least one standard treatment before, be able to take pills, and their organs need to work well. People with brain or spinal metastases, active infections, certain heart conditions, or unresolved severe side effects from previous treatments cannot participate.Inclusion Criteria
I can swallow and keep down pills.
My cancer has a KRAS G12C mutation.
Must have at least 1 measurable lesion per RECIST v1.1
+3 more
Exclusion Criteria
My brain or spinal cancer has been treated and stable for at least 28 days.
QT interval >470 msec
Experiencing unresolved CTCAE 5.0 Grade >1 toxicities
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Dose escalation of JAB-21822 will be administered alone to determine the MTD and RP2D
Up to 4 years
Dose Expansion
Evaluate preliminary antitumor activity when JAB-21822 is administered alone and in combination with cetuximab
Up to 4 years
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The trial is testing JAB-21822 alone and in combination with Cetuximab in patients. Both drugs target different parts of the cancer cells' growth mechanisms. The goal is to see how safe they are and how well patients tolerate them.
3Treatment groups
Experimental Treatment
Group I: Experimental: Arm B, JAB-21822 combination with Cetuximab, Phase 2, Dose ExpansionExperimental Treatment2 Interventions
JAB-21822 will be administered together with Cetuximab in mCRC patients to evaluate the preliminary antitumor activity.
Group II: Arm A1, JAB-21822 monotherapy, Phare 2, Dose ExpansionExperimental Treatment1 Intervention
JAB-21822 will be administered alone at RP2D in selected cancer type patients to evaluate the preliminary antitumor activity.
Group III: Arm A0, JAB-21822 monotherapy, Phase 1, Dose EscalationExperimental Treatment1 Intervention
Dose escalation of JAB-21822 will be administered alone to determine the MTD and RP2D
JAB-21822 is already approved in European Union, United States for the following indications:
🇪🇺 Approved in European Union as Glecirasib for:
- Pancreatic cancer
🇺🇸 Approved in United States as Glecirasib for:
- Pancreatic cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Mayo ClincJacksonville, FL
Mayo ClincPhoenix, AZ
Mayo ClincScottsdale, AZ
University of UtahSalt Lake City, UT
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Who Is Running the Clinical Trial?
Jacobio Pharmaceuticals Co., Ltd.Lead Sponsor
References
Phase II study of cisplatin plus cetuximab in advanced, recurrent, and previously treated cancers of the cervix and evaluation of epidermal growth factor receptor immunohistochemical expression: a Gynecologic Oncology Group study. [2021]The purpose of this study was to evaluate the safety and efficacy of cetuximab (C225), an antibody that inhibits epidermal growth factor receptor (EGFR) activity, with cisplatin and to explore associations between EGFR protein expression with patient demographics or clinical outcome.
Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab. [2022]KRAS mutation is a predictive biomarker for resistance to cetuximab (Erbitux) in metastatic colorectal cancer (mCRC). This study sought to determine if KRAS mutant CRC lines could be sensitized to cetuximab using dasatinib (BMS-354825, Sprycel), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src family kinases (SFKs). We analyzed 16 CRC lines for: (1) KRAS mutation status, (2) dependence on mutant KRAS signaling and (3) expression level of epidermal growth factor receptor (EGFR) and SFKs. From these analyses, we selected three KRAS mutant (LS180, LoVo and HCT116) cell lines and two KRAS wild-type cell lines (SW48 and CaCo2). In vitro, using poly-D-lysine/laminin plates, KRAS mutant cell lines were resistant to cetuximab, whereas KRAS wild-type lines showed sensitivity to cetuximab. Treatment with cetuximab and dasatinib showed a greater antiproliferative effect on KRAS mutant lines when compared with either agent alone in vitro and in vivo. To investigate potential mechanisms for this antiproliferative response in the combinatorial therapy, we performed Human Phospho-Kinase Antibody Array analysis, measuring the relative phosphorylation levels of 39 intracellular proteins in untreated, cetuximab, dasatinib or the combinatorial treatment in the KRAS mutant lines LS180, LoVo and HCT116 cells. The results of this experiment showed a decrease in a broad spectrum of kinases centered on the β-catenin pathway, the mitogen-activated protein kinase (MAPK) pathway, AKT/mammalian target of rapamycin (mTOR) pathway and the family of signal transducers and activators of transcription (STATs) when compared with the untreated control or monotherapy treatments. Next, we analyzed tumor growth with cetuximab, dasatinib or their combination in vivo. KRAS mutant xenografts showed resistance to cetuximab therapy, whereas KRAS wild type demonstrated an antitumor response when treated with cetuximab. KRAS mutant tumors exhibited minimal response to dasatinib monotherapy. However, as in vitro, KRAS mutant lines exhibited a response to the combination of cetuximab and dasatinib. Combinatorial treatment of KRAS mutant xenografts resulted in decreased cell proliferation, as measured by Ki67, and higher rates of apoptosis, as measured by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling). The data presented in this study indicate that dasatinib can sensitize KRAS mutant CRC tumors to cetuximab and may do so by altering the activity of several key signaling pathways. Furthermore, these results suggest that signaling via EGFR and SFKs may be necessary for cell proliferation and survival of KRAS mutant CRC tumors. These data strengthen the rationale for clinical trials combining cetuximab and dasatinib in the KRAS mutant CRC genetic setting.
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. [2023]KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.
EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab. [2022]Cetuximab is a monoclonal epidermal growth factor receptor (EGFR)-targeting antibody, used in the treatment of colon cancer. KRAS mutation status is strongly predictive of cetuximab efficacy, but more predictive factors are needed for better patient selection. PTEN is a downstream inhibitor of the EGFR pathway and has been evaluated as a predictive factor of cetuximab efficacy in colorectal cancer.
Cetuximab in the treatment of patients with colorectal cancer. [2018]Cetuximab is a chimeric mAb with avidity for the EGFR higher than that of the natural ligands of the receptor. Preclinical studies showed that cetuximab demonstrated synergy with topoisomerase I inhibitors in the treatment of human colorectal cancer (CRC) cell lines in vivo. Subsequent clinical trials have shown that cetuximab can reverse resistance to topoisomerase I inhibitors in addition to having modest monotherapy activity. These studies led to accelerated provisional FDA approval of the drug for the treatment of patients with irinotecan-refractory metastatic CRC. Its clinical utility has been improved with the discovery of negative predictive biomarkers; these have shown that there is a lack of cetuximab benefit for patients whose tumors generally harbor a KRAS mutation, thus sparing these patients the toxicity of the agent which would not be of treatment benefit.
Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. [2022]Epidermal growth factor receptor (EGFR) is commonly overexpressed in lung cancer. Cetuximab is a chimeric mouse-human antibody targeted against EGFR. Compared with its inhibitory properties, its immunologic mechanisms have not been well studied. In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC) activity of cetuximab against lung cancer cell lines.
Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. [2022]This multicenter study evaluated the antitumor activity of cetuximab, an immunoglobulin G1 antibody directed at the epidermal growth factor receptor (EGFR), in metastatic colorectal carcinoma (CRC) refractory to irinotecan, oxaliplatin, and a fluoropyrimidine. It also evaluated the safety, pharmacokinetics, immunokinetics, and biologic determinants of activity.
[Efficacy of cetuximab combined with chemotherapy for patients with advanced colorectal cancer and unclear K-ras status]. [2018]To study the efficacy and safety of cetuximab combined with chemotherapy for patients with advanced colorectal cancer (ACRC) and unclear K-ras status.
Assessment of the change in cetuximab-induced antibody-dependent cellular cytotoxicity activity of natural killer cells by steroid. [2022]Epidermal growth factor receptor (EGFR)-targeted therapy has been widely accepted as a promising treatment for solid tumors. Steroid treatment is used to prevent adverse effect of anti-EGFR antibody; however, influence of steroids in the antitumor activity of targeted antibody remains poorly understood. Herein, we demonstrated the impact of steroids in induced antibody-dependent cellular cytotoxicity (ADCC) activity of natural killer (NK) cells by cetuximab.
Impact of cetuximab in current treatment of metastatic colorectal cancer. [2018]Cetuximab is a chimeric monoclonal antibody targeting the EGFR, which has proven effective in patients with metastatic colorectal cancer (mCRC), wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS).
Successful management of infusion reaction accompanying the start of cetuximab therapy. [2018]Cetuximab is a chimeric antibody registered for the therapy of advanced colorectal carcinoma after failure of standard chemotherapy. Rare infusion reactions that resulted in the cessation of therapy have been described after cetuximab administration.
Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. [2022]Cetuximab is a recombinant human/mouse chimeric epidermal growth factor receptor (EGFR) monoclonal antibody. It was approved by the US Food and Drug Administration in February 2004 to be used in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal cancer in patients who had failed to improve with irinotecan-based chemotherapy. Cetuximab was also approved for administration as a single agent in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are intolerant to irinotecan-based chemotherapy.
Distinguishing features of a novel humanized anti-EGFR monoclonal antibody based on cetuximab with superior antitumor efficacy. [2022]Cetuximab, the first approved EGFR targeting therapeutic antibody, is currently used to treat colorectal cancer and head and neck cancer. While effective, cetuximab is associated with a higher rate of skin rash, infusion reactions, and gastrointestinal toxicity, which was suggested to be linked to the presence of heterogeneous glycan contents on the Fab of the SP2/0-produced cetuximab.