JANX008 for Advanced Cancer

Recruiting at 13 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Janux Therapeutics

Must not be taking: EGFR-targeted, CD3 engaging

Disqualifiers: Cardiovascular diseases, Active infection, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This study is a first-in-human (FIH), Phase 1/1b, open-label, multicenter dose escalation and dose expansion study to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity of JANX008 in adult subjects with advanced or metastatic carcinoma expressing EGFR.

Will I have to stop taking my current medications?

The trial requires that you stop any anti-cancer therapy at least 28 days before enrolling. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug JANX008, EGFR-TRACTr for advanced cancer?

EGFR-targeting drugs, like cetuximab and erlotinib, have shown effectiveness in treating certain cancers by blocking the EGFR pathway, which is often overactive in cancers like non-small cell lung cancer and colorectal cancer. These drugs have been used successfully in combination with other treatments, suggesting that targeting EGFR can be a promising strategy in cancer therapy. ^{1 2 3 4 5}

What is known about the safety of EGFR-targeting treatments like JANX008 for advanced cancer?

EGFR-targeting treatments, like those similar to JANX008, often cause skin reactions (like rashes) and digestive issues (like diarrhea) as side effects. These treatments generally do not cause blood-related side effects, but allergic reactions have been noted in a small percentage of cases. ^{1 2 6 7 8}

What makes the drug JANX008 unique for treating advanced cancer?

JANX008 is unique because it targets the retrotranslocation of the Epidermal Growth Factor Receptor (EGFR) to the nucleus, a mechanism not addressed by traditional EGFR inhibitors, which typically focus on blocking the kinase activity of EGFR. This novel approach may be effective in cancers where EGFR is overexpressed and has kinase-independent roles, potentially overcoming resistance seen with other EGFR-targeting therapies. ^{1 3 9 10 11}

Research Team

Janux Therapeutics, MD

Principal Investigator

Janux Therapeutics

Eligibility Criteria

Adults with advanced or metastatic cancers (like lung, kidney, colorectal, or oral cancers) that have progressed despite treatment can join. They must be over 18, have at least one measurable tumor lesion and good organ function. Those who've had certain heart diseases, infections, oxygen therapy, recent cancer treatments or specific prior therapies are excluded.

Inclusion Criteria

My cancer did not respond or I couldn't tolerate all treatments known to help my type of tumor.

I am 18 years old or older.

My cancer is confirmed to be advanced or has spread, including lung, head and neck, colon, or kidney cancer.

Exclusion Criteria

I use supplemental oxygen.

I have previously received EGFR-targeted immune therapy.

I have been treated with CD3 bispecific antibodies before.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Subjects will be dosed weekly during each 21-day cycle to determine the maximum tolerable dose

21 days per cycle

Weekly visits

Dose Expansion

Subjects will be dosed weekly at the preliminary recommended Phase 2 dose (RP2D) during each 21-day cycle

21 days per cycle

Weekly visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 4 years

Treatment Details

Interventions

• JANX008 (Monoclonal Antibodies)

Trial Overview The trial is testing JANX008's safety and effectiveness in treating various advanced cancers expressing a protein called EGFR. It's the first time this drug is being tried in humans to see how it affects tumors and what the body does with it.

Participant Groups

Group I: Expansion Experimental Treatment 1 Intervention

Subjects will be dosed weekly during each 21-day cycle. Subjects will be dosed at the preliminary recommended Phase 2 dose (RP2D).

Group II: Dose Escalation Experimental Treatment 1 Intervention

Subjects will be dosed weekly during each 21-day cycle. Dosage per cohort will increase to determine the maximum tolerable dose.

Group III: Backfill Expansion Experimental Treatment 1 Intervention

Subjects will be dosed weekly during each 21-day cycle. Subjects will be dosed at levels previously declared tolerable.

Who Is Running the Clinical Trial?

Janux Therapeutics

Lead Sponsor

Trials

2

Recruited

240+

Findings from Research

EGFR-targeting agents like C225 and ZD1839 show promise in treating cancers such as non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), with C225 demonstrating synergy with chemotherapy and radiation in preclinical models.

Despite initial positive responses in phase I trials, large phase III studies of ZD1839 combined with chemotherapy did not show an increase in survival for advanced NSCLC patients, highlighting the need for further research into effective treatment combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The epidermal growth factor receptor pathway and its inhibition as anticancer therapy. Janmaat, ML., Giaccone, G.[2022]

EGFR-targeted therapies, such as cetuximab and erlotinib, are important treatments for metastatic cancers, specifically colorectal cancer and non-small cell lung cancer, respectively.

Despite both targeting the same EGFR receptor, cetuximab (a monoclonal antibody) and erlotinib (a small-molecule TKI) have different mechanisms of action, which influence their dosing, toxicity, and potential for use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical implications of the mechanism of epidermal growth factor receptor inhibitors. Marshall, J.[2018]

A new gene therapy protocol targeting cancer cells with high levels of epidermal growth factor receptor (EGFR) was developed, showing effective killing rates of 46.03% in BT-325 cells and 48.12% in Hela cells after 48 hours.

The therapy demonstrated specificity, as it did not affect JK cells that lack EGFR, indicating a targeted approach that could minimize damage to healthy cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A strategy for targeting gene therapy against cancer mediated by epidermal growth factor receptor]. Fang, HS., Hong, M., Zhang, SZ., et al.[2023]

EGFR is a key player in the growth of non-small cell lung cancer (NSCLC), and therapies targeting EGFR, such as cetuximab and small-molecule inhibitors like erlotinib, have shown antitumor activity in previously treated NSCLC patients.

Erlotinib not only improved quality of life but also extended median survival compared to best supportive care, highlighting its efficacy as a single-agent therapy for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of the epidermal growth factor receptor in combined modality treatment for locally advanced non-small cell lung cancer. Ready, N.[2019]

EGFR-related therapies, particularly tyrosine kinase inhibitors like erlotinib and gefitinib, show a clinical benefit of 10-30% in treating non-small cell lung cancer (NSCLC), with better outcomes observed in nonsmoker Asiatic women with EGFR mutations.

Biomarkers such as EGFR mutation status and protein expression are crucial for predicting the effectiveness of EGFR therapies, aiding clinicians in making informed treatment decisions and optimizing resource use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictive and prognostic markers for epidermal growth factor receptor inhibitor therapy in non-small cell lung cancer. Peled, N., Yoshida, K., Wynes, MW., et al.[2022]

Epidermal growth factor receptor (EGFR) targeting agents, such as erlotinib and cetuximab, are effective treatments for various solid tumors, including non-small cell lung carcinoma and metastatic colorectal carcinoma, with increasing use anticipated for other cancers.

These drugs have a unique safety profile with minimal hematological toxicity, but they can cause significant skin and gastrointestinal side effects, which can be managed to improve patient compliance and maintain treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous reactions to anticancer agents targeting the epidermal growth factor receptor: a dermatology-oncology perspective. Lacouture, ME., Melosky, BL.[2018]

Epidermal growth factor receptor (EGFR) inhibitors like erlotinib and gefitinib have shown established clinical activity in treating non-small cell lung cancer, with newer agents like ZD6474 showing promising antitumor activity in clinical trials.

Several new EGFR inhibitors are in advanced testing, indicating that EGFR is a validated target for cancer treatment, and future research will focus on their effectiveness in patients who have not responded to existing EGFR therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Heymach, JV., Nilsson, M., Blumenschein, G., et al.[2018]

Epidermal growth factor receptor (EGFR) inhibitors, including monoclonal antibodies like cetuximab and tyrosine kinase inhibitors like gefitinib, have been approved for cancer treatment, highlighting their efficacy as targeted therapies in epithelial cancers.

Understanding the biology of EGFR interactions can lead to more selective cancer treatments with reduced side effects, although further research is needed to optimize combinations with other therapies and identify the best patient candidates for these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biology of interactions: antiepidermal growth factor receptor agents. Harari, PM., Allen, GW., Bonner, JA.[2022]

The combination of erlotinib and ruxolitinib was well tolerated in 22 patients with EGFR-mutant lung cancers, showing no dose-limiting toxicities and a maximum tolerated dose of 150 mg daily for erlotinib and 20 mg twice daily for ruxolitinib.

Despite the treatment being well tolerated, it was largely ineffective, with only one partial response observed and a median progression-free survival of just 2.2 months, indicating a need for more effective strategies against resistance in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib. Yu, HA., Perez, L., Chang, Q., et al.[2021]

The bivalent recombinant immunotoxin DT390-BiscFv806 shows high cytotoxicity against glioblastoma cells and head and neck squamous cell carcinoma, with IC50 values indicating it is particularly effective against cells expressing EGFRvIII, being 4 orders of magnitude more potent against these cells than against non-expressing cells.

In animal studies, DT390-BiscFv806 significantly inhibited tumor growth in models with U87-EGFRvIII and U87 tumors, achieving growth inhibition rates of 76.3% and 59.4%, respectively, suggesting its potential as a targeted cancer therapy for tumors with high EGFR expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A bivalent recombinant immunotoxin with high potency against tumors with EGFR and EGFRvIII expression. Meng, J., Liu, Y., Gao, S., et al.[2023]

The peptide-based therapeutic cSNX1.3 effectively promotes cell death in EGFR-expressing breast cancer models, leading to significant tumor regression in mice without causing observable toxicity.

cSNX1.3 works by binding to the C-terminus of the EGFR kinase domain, inhibiting its nuclear localization and specifically targeting transformed cancer cells with wildtype EGFR, while sparing normal cells and those with mutant EGFR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sorting nexin-dependent therapeutic targeting of oncogenic epidermal growth factor receptor. Atwell, B., Chen, CY., Christofferson, M., et al.[2023]

References

1. Spain pubmed.ncbi.nlm.nih.gov

The epidermal growth factor receptor pathway and its inhibition as anticancer therapy. [2022]

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

Clinical implications of the mechanism of epidermal growth factor receptor inhibitors. [2018]

3. China pubmed.ncbi.nlm.nih.gov

[A strategy for targeting gene therapy against cancer mediated by epidermal growth factor receptor]. [2023]

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

Inhibition of the epidermal growth factor receptor in combined modality treatment for locally advanced non-small cell lung cancer. [2019]

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

Predictive and prognostic markers for epidermal growth factor receptor inhibitor therapy in non-small cell lung cancer. [2022]

6. Canada pubmed.ncbi.nlm.nih.gov

Cutaneous reactions to anticancer agents targeting the epidermal growth factor receptor: a dermatology-oncology perspective. [2018]

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

Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. [2018]

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

Biology of interactions: antiepidermal growth factor receptor agents. [2022]

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

A Phase 1/2 Trial of Ruxolitinib and Erlotinib in Patients with EGFR-Mutant Lung Adenocarcinomas with Acquired Resistance to Erlotinib. [2021]

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

A bivalent recombinant immunotoxin with high potency against tumors with EGFR and EGFRvIII expression. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Sorting nexin-dependent therapeutic targeting of oncogenic epidermal growth factor receptor. [2023]