MCLA-129 for Non-Small Cell Lung Cancer

Recruiting at 37 trial locations

Overseen By Merus Inquiries

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Merus N.V.

Must not be taking: Steroids, Anticancer, Immunotherapy, others

Disqualifiers: CNS metastases, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Until RECIST progression or initiation of alternative treatment

576 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness and safety of a new treatment, MCLA-129, for individuals with non-small cell lung cancer (NSCLC) and other solid tumors. The study will evaluate the treatment's performance alone or with other therapies, particularly for those whose cancer has worsened after previous treatments. Participants will receive the treatment every two weeks. This trial may suit individuals with NSCLC who have specific genetic mutations (changes in DNA) and have not responded to standard treatments. As a Phase 1/Phase 2 trial, it aims to understand how the treatment works in people and measure its effectiveness in an initial group, offering participants a chance to be among the first to benefit from this innovative approach.

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

The trial requires a washout period (time without taking certain medications) for systemic anticancer therapy or immunotherapy within 4 weeks or 5 half-lives, whichever is shorter, before starting the study drug. For certain chemotherapy agents with delayed toxicity, a 6-week washout period is needed. Please consult with the trial team for specific guidance on your current medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that MCLA-129 was tested for safety in earlier studies. In patients with non-small cell lung cancer (NSCLC), some side effects occurred. About 10% of patients experienced lung-related side effects, such as interstitial lung disease (a condition affecting lung tissue) or pneumonitis (lung inflammation). These side effects ranged from moderate to severe, with one case being very serious.

When combined with Osimertinib, a drug already approved for certain lung cancers, MCLA-129 was generally safe. However, some patients experienced treatment-related side effects, leading them to stop the treatment early.

In studies where MCLA-129 was used with chemotherapy, it showed promise in fighting cancer. Most patients experienced reactions when the drug was administered intravenously, but only a few of these reactions were severe. Skin issues were also common.

Overall, while MCLA-129 has shown potential, there are risks of side effects. It's important to weigh these against the potential benefits and discuss them with a healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for lung cancer?

Researchers are excited about MCLA-129 for non-small cell lung cancer (NSCLC) because it targets the EGFR and cMet pathways, which are key drivers in certain lung cancers. Unlike some existing treatments that may focus on one pathway, MCLA-129 is designed to target both, potentially offering a more comprehensive approach to tackling cancer cells. Additionally, when combined with Osimertinib or chemotherapy, it aims to overcome resistance seen in patients who have become unresponsive to current treatments. This dual-target strategy could lead to more effective treatment options for patients with drug-resistant forms of NSCLC.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research has shown that MCLA-129 has strong and lasting effects in fighting tumors in patients with non-small cell lung cancer (NSCLC) who have specific gene changes, such as METex14 and EGFR mutations. One study found that 82% of patients experienced disease control, meaning their cancer did not worsen for a period. These patients had advanced or metastatic NSCLC, indicating the cancer had spread. The treatment targets EGFR and c-MET proteins, which often promote cancer growth. Early results are promising, suggesting that MCLA-129 might help prevent cancer from worsening in individuals with these mutations. Participants in this trial will receive MCLA-129 in various treatment arms, including those with EGFR exon 20 insertion, cMet exon 14 skipping mutation, and other selected solid tumors, as well as in combination with Osimertinib or chemotherapy for certain resistant cases. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic solid tumors like NSCLC, HNSCC, GC/GEJ, ESCC who've had no luck with standard treatments. They should be relatively healthy (ECOG 0-1), have a life expectancy of at least 12 weeks, and good organ function. People can't join if they've recently used other investigational drugs or therapies, had major surgery or certain cardiovascular issues.

Inclusion Criteria

Serum magnesium within normal ranges (or corrected with supplements)

Hemoglobin ≥9 g/dL

I am fully active or can carry out light work.

Exclusion Criteria

Participation in another clinical study or treatment with any investigational drug within 4 weeks prior to study entry

I have a known history of HIV.

I have a history of serious heart problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Initial dose escalation to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of MCLA-129

4 weeks

Bi-weekly visits for dose administration

Treatment

Participants receive MCLA-129 every two weeks, with some groups also receiving Osimertinib or chemotherapy

Until RECIST progression or initiation of alternative treatment

Bi-weekly visits for infusion, daily oral medication for some groups

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year after treatment

Regular visits for safety assessments and monitoring

What Are the Treatments Tested in This Trial?

Interventions

• MCLA-129

Trial Overview The study tests MCLA-129 alone in patients with various advanced cancers to find the maximum tolerated dose and/or recommended phase two dose. It's an early-phase trial that starts by giving small doses to a few people and increasing it for new groups until doctors find the best dose.

How Is the Trial Designed?

Group I: Part 2 Selected solid tumors with or without an EGFR or cMet alteration Experimental Treatment 1 Intervention

Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D).

Group II: Part 2 NSCLC Third-line or more, osimertinib resistant, platinum resistant (combo with chemotherapy) Experimental Treatment 2 Interventions

Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D) and chemotherapy every three weeks per standard of care according to local guidance.

Group III: Part 2 NSCLC Second-line or more, osimertinib resistant (combo with osimertinib) Experimental Treatment 2 Interventions

Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D) and Osimertinib orally once daily starting at a dose of 80mg.

Group IV: Part 2 NSCLC Second-line or more, osimertinib resistant (combo with chemotherapy) Experimental Treatment 2 Interventions

Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D) and chemotherapy every three weeks per standard of care according to local guidance.

Group V: Part 2 NSCLC Second-line or more harboring cMet exon 14 skipping mutation Experimental Treatment 1 Intervention

Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D).

Group VI: Part 2 NSCLC Second-line or more harboring EGFR exon 20 Insertion Experimental Treatment 1 Intervention

Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D).

Group VII: Part 2 NSCLC First-line harboring EGFR sensitizing mutations Experimental Treatment 2 Interventions

Participants will receive intravenous infusion of MCLA-129 every two weeks at the recommended Phase II dose (RP2D) and Osimertinib orally once daily starting at a dose of 80mg.

Who Is Running the Clinical Trial?

Merus N.V.

Lead Sponsor

Trials

10

Recruited

2,700+

Published Research Related to This Trial

Chemotherapy, typically involving cisplatin or carboplatin combined with a third-generation cytotoxic agent, is the standard treatment for patients with metastatic non-small cell lung cancer who have a good performance score, with a recommended duration of at least 3 to 4 cycles unless the disease progresses.

For older patients over 70 with a good performance score, chemotherapy remains the standard treatment, although the specific regimen is still uncertain; this approach aims to enhance survival and quality of life, especially for those experiencing tumor relapse or disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy for metastased non-small cell lung cancer]. Groen, HJ., Smit, EF., Sleijfer, DT.[2013]

Current standard treatment for advanced non-small-cell lung cancer involves doublet chemotherapy, which has shown 1-year survival rates of approximately 35% and 2-year survival rates of about 15%.

Preliminary studies indicate that triplet therapy may enhance survival rates compared to double therapy, with toxicity rates being low enough to support the development of these three-drug combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triplet combination chemotherapy and targeted therapy regimens. Bunn, PA.[2005]

BCL-XL is identified as the main pro-survival protein in malignant pleural mesothelioma (MPM) cells, and targeting it with BH3-mimetic drugs, especially in combination with MCL-1 inhibition, leads to significant cell death in vitro and improved tumor control in vivo.

The combination of BCL-XL inhibition with standard chemotherapy (Cisplatin) not only enhances cell killing but also improves survival outcomes in animal models, suggesting a promising new treatment strategy for MPM that warrants further clinical investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL-XL is an actionable target for treatment of malignant pleural mesothelioma. Arulananda, S., O'Brien, M., Evangelista, M., et al.[2021]

The study found that cPLA(2)α is expressed in certain non-small lung cancer cell lines (A549 and H460) and is increased in lung cancer tissues, indicating its potential role in cancer progression.

Pyrrolidine-2, a specific inhibitor of cPLA(2)α, showed a dose-dependent reduction in cell growth and activity in these cancer cells, suggesting it could be a promising therapeutic agent for treating non-small lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of the inhibition of cytosolic phospholipase A(2)α in non-small cell lung cancer cells. Sundarraj, S., Kannan, S., Thangam, R., et al.[2021]

Surgery is a potentially curative treatment for non-small cell lung cancer (NSCLC) in stages I and II, and stage IIIA T3 tumors may also be operable with the help of preoperative chemotherapy to downstage the disease.

Postoperative chemotherapy is generally not recommended for stages I, II, and IIIA NSCLC, but cisplatin-based chemotherapy combined with radiotherapy is effective for stage IIIA N2, stage IIIB, and metastatic stage IV NSCLC, improving survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of non-small cell lung cancer according to staging--an update. Lam, WK.[2019]

MCL-1 is crucial for the survival of established breast cancer tumors, as its genetic deletion leads to tumor regression and its inhibition with the BH3-mimetic drug S63845 significantly slows tumor growth.

The anti-tumor effects of targeting MCL-1 are dependent on the pro-apoptotic proteins BAX and BAK, highlighting that MCL-1's primary role in breast cancer is its anti-apoptotic function, which supports the potential effectiveness of MCL-1-specific therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function. Campbell, KJ., Mason, SM., Winder, ML., et al.[2023]

S63845 is a small molecule that effectively targets the MCL1 protein, which is often overexpressed in various cancers, leading to the activation of the mitochondrial apoptotic pathway and the death of MCL1-dependent cancer cells.

In preclinical studies, S63845 demonstrated strong anti-tumor activity with a good safety profile, suggesting its potential as a treatment for multiple myeloma, leukemia, lymphoma, and other solid tumors, either alone or in combination with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Kotschy, A., Szlavik, Z., Murray, J., et al.[2022]

Complex 9 is a novel platinum-based inhibitor that specifically targets Mcl-1 in the mitochondria of tumor cells, showing high binding affinity and enhanced antitumor efficacy.

In mouse models, Complex 9 effectively induced apoptosis in cancer cells and worked synergistically with ABT-199 to overcome resistance, indicating its potential as a promising treatment strategy for tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platinum-Based Mcl-1 Inhibitor Targeting Mitochondria Achieves Enhanced Antitumor Activity as a Single Agent or in Combination with ABT-199. Lu, X., Wu, MF., Wu, JL., et al.[2023]

The combination of AMG-510 and cisplatin significantly enhances anti-tumor effects in lung adenocarcinoma with KRAS G12C mutations, showing more than double the tumor size reduction compared to either drug alone in in vivo experiments.

In vitro studies revealed that the combination therapy resulted in lower IC50 values and fewer tumor cell colonies, indicating improved efficacy and potential mechanisms involving the PI3K-Akt signaling pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AMG-510 and cisplatin combination increases antitumor effect in lung adenocarcinoma with mutation of KRAS G12C: a preclinical and translational research. Wu, LL., Jiang, WM., Liu, ZY., et al.[2023]

MCL1 knockdown alone did not trigger apoptosis in KRAS-mutant lung adenocarcinoma cells, but when combined with the MEK inhibitor trametinib, it significantly enhanced cell death and reduced tumor growth in vivo.

Dual inhibition of MCL1 and Bcl-xL led to extensive apoptosis in both KRAS-mutant and EGFR-mutant lung adenocarcinoma cell lines, suggesting a promising therapeutic strategy for these cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MCL1 inhibition enhances the therapeutic effect of MEK inhibitors in KRAS-mutant lung adenocarcinoma cells. Tada, M., Sumi, T., Tanaka, Y., et al.[2020]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.8604

Efficacy and safety of MCLA-129, an EGFR/c-MET ... MCLA-129 demonstrates robust and durable antitumor activity in patients with NSCLC harboring METex14, EGFR exon20ins and sensitized EGFR mutations.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.8583

Efficacy and safety of MCLA-129, an anti-EGFR/c-MET ... Preliminary data are presented of patients (pts) with advanced or metastatic METex14 NSCLC treated with MCLA-129 in the dose expansion phase of ...

3. annalsofoncology.org annalsofoncology.org/article/S0923-7534(23)04801-9/fulltext

516MO Efficacy and safety of MCLA-129, an anti-EGFR/c- ... DCR was 82% (95% CI 60-95). In 48 pts treated, the most common AEs regardless of causality were IRRs (composite term) in 85% of pts (6% ≥G3). Skin toxicity was ...

4. merus.nl merus.nl/wp-content/uploads/2023/12/NSCLC-ESMO-Asia-Mini-Oral-MOZ-76522_v3.0_01Dec23_final.pdf

Efficacy and safety of MCLA-129, an EGFR x c-MET ... *ORR is the proportion of confirmed and unconfirmed responders out of the primary efficacy analysis population in 1L NSCLC patients with EGFR ...

5. aacrjournals.org aacrjournals.org/cancerres/article/85/8_Supplement_1/5921/759345/Abstract-5921-Correlation-between-MET

Abstract 5921: Correlation between MET amplification ... Correlation between MET amplification/overexpression status and response to MCLA-129 in advanced non-small-cell lung cancer (NSCLC): biomarker ...

6. merus.nl merus.nl/wp-content/uploads/2024/06/MCLA-129-poster-ASCO2024-FINAL.pdf

Efficacy and Safety of MCLA-129, an Anti-EGFR/c-MET ... Efficacy and Safety of MCLA-129, an Anti-EGFR/c-MET Bispecific Antibody, in Non-Small Cell Lung Cancer. (NSCLC) With Hepatocyte Growth Factor Receptor (c-MET) ...

7. asco.org asco.org/abstracts-presentations/ABSTRACT454344

Efficacy and safety of MCLA-129, an EGFR/c-MET ... Efficacy and safety of MCLA-129, an EGFR/c-MET bispecific antibody, in advanced non-small cell lung cancer (NSCLC). ; ORR* (95% CI), 43.5% (23.2%-65.5%), 37.5% ( ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT04868877

NCT04868877 | Phase 1/2 Study Evaluating MCLA-129, a ... Phase 1/​2 Study Evaluating MCLA-129, a Human Anti-EGFR, Anti-c-MET Bispecific Antibody, in Advanced NSCLC and Other Solid Tumors, Alone and in Combination.