MET-4 for Cancer

(MET4-IO Trial)

Overseen By Lillian Siu, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University Health Network, Toronto

Must be taking: Immune checkpoint inhibitors

Disqualifiers: Gastrointestinal disorders, Pregnancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 1 year

65 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if adding beneficial gut bacteria to a standard cancer treatment can help the immune system fight cancer better. It focuses on patients who are already receiving cancer treatment but are not responding well. The beneficial bacteria may boost the immune response, enhancing the effectiveness of the cancer medicine.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it seems that participants are expected to continue their standard immune checkpoint inhibitor treatment.

What data supports the effectiveness of the drug MET-4 for cancer?

Research shows that drugs targeting the MET pathway, like MET-4, can be effective in treating cancers with MET dysregulation, as this pathway is often linked to tumor growth and poor outcomes. MET inhibitors have shown promise in improving survival in patients with certain types of lung cancer, suggesting potential benefits for other cancers as well. ^{1 2 3 4 5}

What safety data exists for MET-4 treatment in humans?

MET-4, also known as AMG 337, has been tested in humans with advanced solid tumors. In these studies, common side effects included headache and nausea, but no severe dose-limiting toxicities were reported. The safety profile of MET inhibitors, like AMG 337, is generally consistent across different patient populations. ^{6 7 8 9 10}

How does the drug MET-4 differ from other cancer treatments?

MET-4 is unique because it targets the MET receptor, which is often overactive in certain cancers, leading to tumor growth and spread. Unlike some other treatments, MET-4 specifically inhibits various mutant forms of MET, including those resistant to other MET inhibitors, making it a promising option for cancers with MET mutations. ^{11 12 13 14 15}

Research Team

Lillian Siu, MD

Principal Investigator

Princess Margaret Cancer Centre

Anna Spreafico, MD PhD

Principal Investigator

Princess Margaret Cancer Centre

Eligibility Criteria

Adults with advanced solid tumors who are either starting or already on anti-PD-1/PD-L1 immunotherapy, not part of another clinical trial. They must be able to provide tissue samples, stool and blood for analysis, have measurable disease, and a performance status of 0-2. Women must not be pregnant. Those with gastrointestinal disorders affecting absorption cannot join.

Inclusion Criteria

Be willing and able to provide stool and blood specimen for analyses at protocol specified time points.

I can take care of myself and am up and about more than half of my waking hours.

I have previously received immunotherapy.

Exclusion Criteria

Pregnant or planning to get pregnant in the next 6 months.

Any condition that, in the opinion of the Investigator, would interfere with subject safety, or evaluation of the collected specimen and interpretation of study result.

I can swallow pills and don't have gut issues affecting drug absorption, except I may have a colostomy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-in Period

MET-4 is initiated as a run-in for a minimum of 1 week, and maximum of 2 weeks before ICI administration

1-2 weeks

Treatment

Participants receive MET-4 in combination with immune checkpoint inhibitors (ICIs) until unacceptable toxicity, confirmed progression of disease, or completion of 1 year of ICI

Up to 1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 weeks

Treatment Details

Interventions

• MET-4

Trial Overview The study is testing MET-4's safety and its ability to integrate into the body when used with standard immune checkpoint inhibitors (ICIs). Participants are divided into groups: one receiving MET-4 plus ICI therapy; others getting only ICI therapy; some who've seen disease progression on ICIs may also receive MET-4.

Participant Groups

Group I: Group D Experimental Treatment 1 Intervention

In group D, eligible subjects with stage III or resected stage IV melanoma who are to start adjuvant ICI, will be randomized in a 1:1 ratio to receive MET-4 in addition to anti-PD1 antibody +/- anti-CTLA4 antibody as per SOC or control group. Patients will be stratified per BRAF mutation status. Subjects will be administered the same MET-4 dose as subjects in groups A, B and C. MET-4 will be initiated as run-in for a minimum of 1 week, and maximum of 2 weeks before ICI administration. MET-4 will be continued until unacceptable toxicity, confirmed PD by RECIST v1.1 or completion of 1 year of ICI, whichever occurs earlier. Subjects in the control arms of groups B, C and D will be treated with ICI therapy as per institution standard of care without MET-4.

Group II: Group C Experimental Treatment 1 Intervention

In group C, eligible subjects with advanced solid tumors whom are already on ICI with first unconfirmed PD on evaluation scans per investigator's assessment, will be randomised in a 1:1 ratio to receive MET-4 in addition to the PD-1/PD-L1 inhibitor as per SOC or control group. These subjects must be clinically stable and are to be continued on ICI at the discretion of the investigator. There will be no run-in period for this cohort. Subjects will be administered the same MET-4 dose as subjects in groups A and B.

Group III: Group B Experimental Treatment 1 Intervention

Eligible subjects with advanced solid tumors starting ICI will be randomised in a 3:1 ratio stratifying for prior IO exposure, to receive MET-4 together with any approved PD-1/PD-L1 inhibitor as per SOC or control group. There will be a run-in period for subjects in the MET-4 treatment group. Following the run-in period of ICI therapy, subjects will be administered the same MET-4 dose as subjects in group A.

Group IV: Group A: Safety Cohort Experimental Treatment 1 Intervention

Subjects with advanced solid tumors already on ICI will receive treatment with MET-4 in addition to SOC ICI. MET-4 is administered orally as an initial daily loading dose (5g) of MET-4 over 2 days followed by a daily maintenance dose (1.5g) of MET-4 and will be continued until unacceptable toxicity, progression of disease

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

NuBiyota

Collaborator

Trials

9

Recruited

240+

Findings from Research

In a phase II trial, capmatinib, a MET inhibitor, showed a high response rate of 72% in treatment-naïve patients, indicating its potential effectiveness in early-stage treatment.

For previously treated patients, the response rate was lower at 39.1%, and common side effects included peripheral edema, nausea, and vomiting, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capmatinib Triggers Responses in NSCLC. [2019]

AMG 337, a MET inhibitor, was well-tolerated in a small study of 11 Asian patients with advanced solid tumors, showing no dose-limiting toxicities and common side effects like headache (73%) and nausea (45%).

The pharmacokinetics of AMG 337 were consistent with previous studies in Western populations, and while one patient experienced a partial response, the study was terminated early, indicating the need for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 study evaluating AMG 337 in Asian patients with advanced solid tumors. Yasui, H., Go, N., Yang, H., et al.[2022]

AMG 337, an oral MET inhibitor, was found to be tolerable with manageable side effects, establishing a maximum tolerated dose of 300 mg once daily in a study involving 111 patients with advanced solid tumors.

The treatment showed a promising objective response rate of 29.6% in patients with MET-amplified tumors, suggesting potential efficacy that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors. Hong, DS., LoRusso, P., Hamid, O., et al.[2023]

References

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

Improved Survival Outcomes in Patients With MET-Dysregulated Advanced NSCLC Treated With MET Inhibitors: Results of a Multinational Retrospective Chart Review. [2023]

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

Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist. [2020]

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

Prognostic impact of tumor MET expression among patients with stage IV gastric cancer: a Danish cohort study. [2022]

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

Prognostic value of c-Met in colorectal cancer: a meta-analysis. [2018]

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

MET: a promising anticancer therapeutic target. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Characteristics of Phase IV Clinical Trials in Oncology: An Analysis Using the ClinicalTrials.gov Registry Data. [2023]

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

Capmatinib Triggers Responses in NSCLC. [2019]

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

A Phase 1 study evaluating AMG 337 in Asian patients with advanced solid tumors. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and Tolerability of c-MET Inhibitors in Cancer. [2023]

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

Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors. [2023]

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

NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its constitutively active mutants. [2021]

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

Foretinib is effective therapy for metastatic sonic hedgehog medulloblastoma. [2015]

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

Drug development of MET inhibitors: targeting oncogene addiction and expedience. [2022]

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

Targeting MET Dysregulation in Cancer. [2023]

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

An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. [2022]