TNO155 +/- Nazartinib for Advanced Cancers

Recruiting at 20 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Novartis Pharmaceuticals

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: KRAS, Cardiac disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

227 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently using immunosuppressive agents or chronic corticosteroids.

What data supports the effectiveness of the drug TNO155 in combination with nazartinib for advanced cancers?

Nazartinib, a component of the treatment, has shown effectiveness in targeting specific mutations in non-small-cell lung cancer, particularly those resistant to earlier treatments. This suggests potential benefits when used in combination with other drugs like TNO155 for advanced cancers. ^{1 2 3 4 5}

Is the combination of TNO155 and nazartinib safe for humans?

Nazartinib has shown manageable safety in patients with advanced non-small cell lung cancer, meaning it was generally well-tolerated with side effects that could be managed. ^{3 6 7 8 9}

How is the drug TNO155 combined with nazartinib different from other treatments for advanced cancers?

The combination of TNO155 with nazartinib is unique because it targets specific mutations in cancer cells, potentially overcoming resistance seen with earlier treatments. Nazartinib is a third-generation drug that specifically inhibits mutated forms of the EGFR protein, which are common in certain advanced cancers, while sparing normal cells, potentially reducing side effects. ^{1 3 9 10 11}

What is the purpose of this trial?

The purpose of this first in human (FIH) trial is to characterize the safety and tolerability of the SHP2 inhibitor TNO155 alone and in combination with EGF816 (nazartinib) and identify a recommended dose for future studies in adult patients with advanced solid tumors in selected indications.

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

Adults over 18 with advanced solid tumors like melanoma or lung cancer, who've tried standard treatments without success or can't tolerate them. They must understand the study and follow its schedule, agree to effective contraception, and have an acceptable level of physical function (ECOG ≤2). People with certain viral infections, specific genetic mutations in their tumors, significant health issues including heart disease, eye conditions that increase injury risk, active severe skin disorders or bowel inflammation are excluded.

Inclusion Criteria

I have been tested for Hepatitis B and C.

I can perform daily activities with minimal assistance.

My condition worsened after standard treatment, or standard treatments aren't suitable for me.

Exclusion Criteria

You have a history of being HIV positive.

Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.

I have a serious heart condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive TNO155 alone or in combination with EGF816 (nazartinib) to determine the maximum tolerated dose

21-28 days per cycle

At least once per treatment cycle

Dose Expansion

Participants receive the recommended dose of TNO155 alone or in combination with EGF816 (nazartinib) to further evaluate safety and efficacy

Until disease progression or unacceptable toxicity

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 months

Treatment Details

Interventions

• TNO155
• TNO155 in combination with EGF816 (nazartinib)

Trial Overview The trial is testing TNO155 alone and combined with EGF816 (nazartinib) to find safe doses for future studies. It's a first-in-human study focusing on safety and tolerability in patients with selected types of advanced solid tumors. The goal is also to determine the recommended dose levels for subsequent research phases.

Participant Groups

Group I: TNO155 in combination with EGF816 (nazartinib) Experimental Treatment 1 Intervention

TNO155 in combination with EGF816 (nazartinib) in patients with advanced EGFR mutant NSCLC

Group II: TNO155 Experimental Treatment 1 Intervention

TNO155 for oral administration

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Findings from Research

Gefitinib, an EGFR inhibitor, was effective in shrinking tumors in two patients with advanced non-small cell lung carcinoma (NSCLC) before they underwent surgery, demonstrating its potential as a preoperative treatment.

Both patients experienced significant tumor reduction and underwent potentially curative surgeries, but they relapsed after stopping adjuvant gefitinib therapy, indicating the need for further research on long-term outcomes and survival benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Down-staging of EGFR mutation-positive advanced lung carcinoma with gefitinib followed by surgical intervention: follow-up of two cases. Levchenko, EV., Moiseyenko, VM., Matsko, DE., et al.[2018]

The ARTEMIS study shows that combining the VEGF inhibitor bevacizumab with the EGFR inhibitor erlotinib significantly improves progression-free survival in patients with EGFR mutant non-small-cell lung cancer by over 6 months.

Patients with brain metastases and the EGFR L858R mutation experienced even greater benefits, highlighting the importance of personalized treatment strategies in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ARTEMIS highlights VEGF inhibitors as effective partners for EGFR TKIs in EGFR mutant NSCLC. Le, X., Nilsson, MB., Robichaux, JP., et al.[2021]

In a study involving 73 patients with advanced EGFR-mutant non-small-cell lung cancer (NSCLC), the combination of tepotinib and gefitinib showed promising efficacy, particularly in patients with high MET overexpression or MET amplification, leading to longer progression-free survival (PFS) compared to standard chemotherapy.

The treatment was generally well-tolerated, with no dose-limiting toxicities observed, although some patients experienced grade 3 or worse adverse events, such as increased amylase and lipase levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial. Wu, YL., Cheng, Y., Zhou, J., et al.[2020]

References

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

Heterogeneity and Coexistence of T790M and T790 Wild-Type Resistant Subclones Drive Mixed Response to Third-Generation Epidermal Growth Factor Receptor Inhibitors in Lung Cancer. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Down-staging of EGFR mutation-positive advanced lung carcinoma with gefitinib followed by surgical intervention: follow-up of two cases. [2018]

3. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of nazartinib (EGF816) in adults with EGFR-mutant non-small-cell lung carcinoma: a multicentre, open-label, phase 1 study. [2020]

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

ARTEMIS highlights VEGF inhibitors as effective partners for EGFR TKIs in EGFR mutant NSCLC. [2021]

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

Combined Pan-HER and ALK/ROS1/MET Inhibition with Dacomitinib and Crizotinib in Advanced Non-Small Cell Lung Cancer: Results of a Phase I Study. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Nazartinib for treatment-naive EGFR-mutant non-small cell lung cancer: Results of a phase 2, single-arm, open-label study. [2022]

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

A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial. [2020]

9. Ireland pubmed.ncbi.nlm.nih.gov

Central nervous system efficacy of rezivertinib (BPI-7711) in advanced NSCLC patients with EGFR T790M mutation: A pooled analysis of two clinical studies. [2023]

10. Korea (South) pubmed.ncbi.nlm.nih.gov

Lazertinib: on the Way to Its Throne. [2022]

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

Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1-2 study. [2020]