JAB-21822 + Cetuximab for Solid Tumors

Recruiting at 3 trial 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. ^{1 2 3 4 5}

What 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. ^{3 6 7 8 9}

Is 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. ^{6 10 11 12 13}

Eligibility 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

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

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

Treatment Details

Interventions

• Cetuximab (EGFR inhibitor)
• JAB-21822 (KRAS G12C inhibitor)

Trial Overview 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.

Participant Groups

Group I: Experimental: Arm B, JAB-21822 combination with Cetuximab, Phase 2, Dose Expansion Experimental Treatment 2 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 Expansion Experimental Treatment 1 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 Escalation Experimental Treatment 1 Intervention

Dose escalation of JAB-21822 will be administered alone to determine the MTD and RP2D

Who Is Running the Clinical Trial?

Jacobio Pharmaceuticals Co., Ltd.

Lead Sponsor

Trials

21

Recruited

2,300+

Findings from Research

The combination of cetuximab and cisplatin was found to be safe for women with advanced cervical cancer, with manageable side effects, but did not show improved tumor response compared to cisplatin alone, as only 9% and 16% of patients responded in the prior chemotherapy and no chemotherapy groups, respectively.

EGFR protein was expressed in 98% of the tumors analyzed, suggesting that while the treatment was tolerated, the expected benefit from targeting EGFR with cetuximab was not realized in terms of enhanced efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Farley, J., Sill, MW., Birrer, M., et al.[2021]

KRAS mutations in colorectal cancer (CRC) are linked to resistance against cetuximab, but combining cetuximab with dasatinib can enhance the drug's effectiveness against KRAS mutant tumors, as shown in both in vitro and in vivo studies.

The combination treatment led to decreased cell proliferation and increased apoptosis in KRAS mutant tumors, suggesting that dasatinib alters key signaling pathways, making these tumors more responsive to cetuximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab. Dunn, EF., Iida, M., Myers, RA., et al.[2022]

The combination of divarasib and cetuximab in treating KRAS G12C-positive colorectal cancer showed a manageable safety profile, with only 13.8% of patients experiencing treatment-related adverse events that required dose reductions, and no treatment withdrawals.

This combination therapy demonstrated promising antitumor activity, achieving a 62.5% objective response rate in previously untreated patients, with a median progression-free survival of 8.1 months, indicating its potential effectiveness in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. Desai, J., Alonso, G., Kim, SH., et al.[2023]

In a study of 226 patients with advanced colorectal cancer treated with cetuximab, EGFR gain was associated with better treatment outcomes, indicating that higher levels of EGFR may enhance the drug's efficacy.

PTEN protein expression was linked to longer time to progression in patients with wild-type KRAS, especially those with elevated amphiregulin levels, suggesting that maintaining PTEN function could be crucial for optimizing cetuximab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab. Razis, E., Pentheroudakis, G., Rigakos, G., et al.[2022]

Cetuximab shows modest efficacy as a single-agent treatment for metastatic colorectal cancer (CRC) in patients without KRAS mutations, and it can improve overall and progression-free survival when combined with irinotecan in first-line therapy.

The identification of KRAS mutations serves as a negative predictive biomarker, helping to avoid unnecessary toxicity in patients who are unlikely to benefit from cetuximab, thus enhancing the drug's clinical utility.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab in the treatment of patients with colorectal cancer. Garrett, CR., Eng, C.[2018]

Cetuximab, an antibody targeting the EGFR, effectively triggers antibody-dependent cellular cytotoxicity (ADCC) against lung cancer cells, even at low concentrations, indicating its potential as an immunotherapy.

The study found that ADCC activity is significantly enhanced by interleukin-2, particularly through the activation of natural killer (NK) cells, and is less affected by chemotherapy, suggesting a robust immunologic mechanism for cetuximab in treating lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Kurai, J., Chikumi, H., Hashimoto, K., et al.[2022]

Cetuximab demonstrated antitumor activity in patients with metastatic colorectal carcinoma (CRC) who were resistant to standard treatments, achieving a response rate of approximately 12.4% in a study of 346 patients.

The treatment was generally well tolerated, with a high incidence of acneiform rash (82.9%), which correlated with better treatment efficacy, while EGFR mutations and gene amplification did not significantly influence the response to cetuximab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. Lenz, HJ., Van Cutsem, E., Khambata-Ford, S., et al.[2022]

Cetuximab combined with chemotherapy shows a good overall response rate (43.1%) and overall survival (28.5 months) in patients with advanced colorectal cancer and unclear K-ras status, based on a study of 102 patients.

The treatment is considered safe, with common side effects including acneiform eruptions and neutropenia, but no treatment-related deaths were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of cetuximab combined with chemotherapy for patients with advanced colorectal cancer and unclear K-ras status]. Guo, GF., Xia, LP., Qiu, HJ., et al.[2018]

Steroid treatment, specifically dexamethasone, significantly inhibits the antibody-dependent cellular cytotoxicity (ADCC) activity of natural killer (NK) cells when used with the anti-EGFR antibody cetuximab, which is important for treating solid tumors like head and neck squamous cell carcinoma and colon cancer.

Dexamethasone also reduces the expression of activation markers on NK cells, suggesting that while steroids are used to prevent side effects of anti-EGFR therapy, they may negatively impact the effectiveness of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessment of the change in cetuximab-induced antibody-dependent cellular cytotoxicity activity of natural killer cells by steroid. Kumai, T., Oikawa, K., Aoki, N., et al.[2022]

Cetuximab is an effective treatment for patients with metastatic colorectal cancer (mCRC) who have wild-type KRAS, and its use has been supported by various clinical trials assessing its impact on patient outcomes and quality of life.

The identification of KRAS mutation status is crucial for selecting patients who are most likely to benefit from cetuximab, enhancing the treatment's efficacy in managing unresectable mCRC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of cetuximab in current treatment of metastatic colorectal cancer. Sotelo Lezama, MJ., Sastre Valera, J., Díaz-Rubio García, E.[2018]

Cetuximab, a treatment for advanced colorectal cancer, can cause severe infusion reactions, including loss of consciousness, but therapy can be continued safely with proper management.

In two observed cases, patients experienced serious reactions but were successfully treated with corticosteroids and monitored in the intensive care unit, demonstrating that cetuximab can still provide therapeutic benefits even after such reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful management of infusion reaction accompanying the start of cetuximab therapy. Melichar, B., Cerman, J., Malírová, E.[2018]

Cetuximab has demonstrated significant efficacy in treating metastatic colorectal cancer, achieving a partial response in 10.8% of patients receiving it alone and 22.9% when combined with irinotecan, based on a Phase III trial involving 329 patients.

The drug is generally well tolerated, with common side effects like acnelike rash and hypersensitivity reactions, but the lack of reliable predictive markers for patient selection remains a challenge for its clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. Wong, SF.[2022]

HLX07, a re-engineered version of cetuximab, maintains similar binding affinity to EGFR but demonstrates improved bioactivity and reduced toxicity in preclinical studies, suggesting it may be a more effective treatment option.

In a preliminary phase 1 study, HLX07 showed a lower incidence of severe skin rashes compared to cetuximab, indicating a potential for better tolerability in patients undergoing EGFR-targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Distinguishing features of a novel humanized anti-EGFR monoclonal antibody based on cetuximab with superior antitumor efficacy. Lin, PH., Tseng, CL., Cheng, YC., et al.[2022]

References

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

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]

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

Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab. [2022]

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

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. [2023]

4. Germany pubmed.ncbi.nlm.nih.gov

EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Cetuximab in the treatment of patients with colorectal cancer. [2018]

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

Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. [2022]

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

Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. [2022]

8. China pubmed.ncbi.nlm.nih.gov

[Efficacy of cetuximab combined with chemotherapy for patients with advanced colorectal cancer and unclear K-ras status]. [2018]

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

Assessment of the change in cetuximab-induced antibody-dependent cellular cytotoxicity activity of natural killer cells by steroid. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Impact of cetuximab in current treatment of metastatic colorectal cancer. [2018]

11. Germany pubmed.ncbi.nlm.nih.gov

Successful management of infusion reaction accompanying the start of cetuximab therapy. [2018]

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

Cetuximab: an epidermal growth factor receptor monoclonal antibody for the treatment of colorectal cancer. [2022]

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

Distinguishing features of a novel humanized anti-EGFR monoclonal antibody based on cetuximab with superior antitumor efficacy. [2022]