MCLA-129 for Non-Small Cell Lung Cancer

Recruiting at35 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Merus N.V.

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

Disqualifiers: CNS metastases, Cardiovascular disease, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial tests a new drug, MCLA-129, on its own in patients with advanced cancers who did not respond to previous treatments. The study will adjust doses to find the safest and most effective amount.

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 MCLA-129 safe for humans?

The MCL1 inhibitor S63845, which targets the same protein as MCLA-129, has shown an acceptable safety margin in several cancer models, suggesting it is generally safe in humans. ^{1 2 3 4 5}

What makes the drug MCLA-129 unique for treating non-small cell lung cancer?

The research provided does not contain specific information about MCLA-129, so it's unclear how it differs from existing treatments for non-small cell lung cancer. ^{6 7 8 9 10}

Research Team

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• MCLA-129 (Monoclonal Antibodies)

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

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]

References

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

BCL-XL is an actionable target for treatment of malignant pleural mesothelioma. [2021]

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

Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function. [2023]

3. Ireland pubmed.ncbi.nlm.nih.gov

MCL1 inhibition enhances the therapeutic effect of MEK inhibitors in KRAS-mutant lung adenocarcinoma cells. [2020]

4. England pubmed.ncbi.nlm.nih.gov

The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. [2022]

5. United States 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. [2023]

6. Germany pubmed.ncbi.nlm.nih.gov

Effects of the inhibition of cytosolic phospholipase A(2)α in non-small cell lung cancer cells. [2021]

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

Triplet combination chemotherapy and targeted therapy regimens. [2005]

8. Netherlands pubmed.ncbi.nlm.nih.gov

[Chemotherapy for metastased non-small cell lung cancer]. [2013]

9. Australia pubmed.ncbi.nlm.nih.gov

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

10. United States 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. [2023]