ISM3412 for Cancer

Recruiting at 3 trial locations

Overseen By Maile Krumpschmidt

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: InSilico Medicine Hong Kong Limited

Must not be taking: MAT2A inhibitors, PRMT inhibitors

Disqualifiers: Other tumors, CNS tumors, others

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

Compensation: Varies

Number of Visits: Unknown

80 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had anti-tumor therapy within 28 days before starting the trial, and you cannot participate in other clinical studies during this time.

What data supports the effectiveness of the drug ISM3412 for cancer treatment?

The I-PREDICT study suggests that personalized treatment with combination therapies, which may include drugs like ISM3412, can improve outcomes in cancer patients by targeting more molecular alterations, leading to better disease control and longer survival rates. ^{1 2 3 4 5}

What safety data exists for ISM3412 or similar molecular target anticancer drugs?

Molecular target anticancer drugs, like ISM3412, have been shown to increase the risk of serious adverse events (SAEs) and fatal adverse events (FAEs) compared to placebo. In a large analysis, the risk of SAEs was 1.57 times higher and FAEs 1.51 times higher for these drugs, indicating a need for careful monitoring. ^{6 7 8 9 10}

How is the drug ISM3412 different from other cancer treatments?

ISM3412 may be unique because it could involve a mechanism similar to dual inhibitors like LY2780301 and M2698, which target the PI3K/AKT/mTOR pathway, a key player in cancer cell growth and resistance to therapy. This pathway is not targeted by all cancer treatments, making ISM3412 potentially novel in its approach. ^{11 12 13 14 15}

What is the purpose of this trial?

The study has consists of two parts, a dose escalation part (Part 1) and a dose selection optimization part (Part 2). The primary objectives of this study are to evaluate the safety and tolerability of ISM3412 in participants with locally advanced/metastatic solid tumors, and to determine the RP2D of ISM3412.

Eligibility Criteria

This trial is for adults with advanced solid tumors that can't be surgically removed, have worsened after standard treatment, or have no standard treatment available. Participants must show evidence of a specific genetic change (MTAP deletion) in their tumor and meet health and safety criteria.

Inclusion Criteria

I am fully active and can carry on all pre-disease activities without restriction.

I can sign the consent form and follow the study's requirements.

My doctor believes I have at least 12 weeks to live.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive ISM3412 once daily in sequential cohorts of increasing doses to evaluate safety and tolerability

31 days

Dose Selection Optimization

Participants are randomized to receive one of the two selected dose levels of ISM3412 once daily

Approximately 30 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ISM3412

Trial Overview The study tests ISM3412's safety and tolerability in two parts: finding the highest dose patients can take without serious side effects (Part 1), then optimizing the best dose to use (Part 2). It aims to find the right dosage for future studies.

Participant Groups

Group I: Part 2 Dose Selection Optimization Experimental Treatment 1 Intervention

Participants will be randomized to receive one of the two selected dose levels of ISM3412 once daily determined by Study Review Committee.

Group II: Part 1 Dose Escalation Experimental Treatment 1 Intervention

Patients will receive ISM3412 once daily in sequential cohorts of increasing doses.

Who Is Running the Clinical Trial?

InSilico Medicine Hong Kong Limited

Lead Sponsor

Trials

9

Recruited

1,100+

Findings from Research

Recent advancements in the treatment of metastatic breast cancer emphasize the importance of using patient and tumor-specific biomarkers to tailor individualized therapies, enhancing the potential for more effective treatments.

The PRAEGNANT study network is addressing the challenges of personalized medicine by creating a professional infrastructure that supports the integration of molecular tumor data into clinical studies, while still prioritizing patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biomarkers in Patients with Metastatic Breast Cancer and the PRAEGNANT Study Network. Fasching, PA., Brucker, SY., Fehm, TN., et al.[2022]

In a study of 1,000 patients who underwent FoundationOne CDx™ testing, 652 had actionable mutations, and 38 received targeted therapies, showing a disease control rate of 41.2% with some patients achieving partial responses.

The median progression-free survival was 2.7 months and median overall survival was 9.9 months, indicating that while targeted therapies based on genetic alterations can be beneficial, further research is needed to fully understand their efficacy in community oncology settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of Precision Medicine on Clinical Outcomes: A Single-Institution Retrospective Study. Quinn, R., Patel, R., Sison, C., et al.[2023]

The developed gene expression sensitivity profiles can accurately predict patient responses to PARP inhibitors, outperforming traditional biomarkers like BRCA1/2 mutation status in identifying sensitive cancer cell lines and patient-derived tumors.

These drug sensitivity signatures not only predict responses to existing therapies but also help identify new drug combinations that could enhance treatment efficacy, potentially improving patient outcomes in cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved prediction of PARP inhibitor response and identification of synergizing agents through use of a novel gene expression signature generation algorithm. McGrail, DJ., Lin, CC., Garnett, J., et al.[2020]

Novel clinical trial designs like umbrella, basket, and adaptive enrichment strategies are being developed to speed up drug testing in oncology, allowing for more precise targeting of therapies to specific patient groups.

These designs require advanced statistical methods and collaboration across multiple disciplines, highlighting the need for improved infrastructure and data technologies to effectively implement and interpret trial results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving Clinical Trial Efficiency: Thinking outside the Box. Mandrekar, SJ., Dahlberg, SE., Simon, R.[2022]

In a prospective study involving patients with refractory malignancies, personalized treatment using combination therapies was feasible, with 49% of patients receiving tailored multidrug regimens.

Higher 'matching scores' from targeting more molecular alterations were associated with significantly better disease control and longer progression-free and overall survival rates, suggesting that combination therapies may enhance outcomes compared to traditional single-drug approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Sicklick, JK., Kato, S., Okamura, R., et al.[2021]

A meta-analysis of 53 Phase II/III/IV trials involving nearly 20,000 patients revealed that molecular target anticancer drugs significantly increase the risk of serious adverse events (SAEs) by 57% and fatal adverse events (FAEs) by 51% compared to placebo.

The overall incidence rates for SAEs and FAEs were found to be 26.9% and 2.3%, respectively, highlighting the need for careful monitoring and preventive measures for patients receiving these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis. Wang, Z., Yang, X., Wang, J., et al.[2020]

Immune checkpoint inhibitors (ICIs) can lead to immune-related adverse events (irAEs) due to their mechanism of action, necessitating a multidisciplinary approach for effective patient management, as highlighted by 30 real-world pharmacovigilance studies.

These studies have provided valuable insights into the patterns, kinetics, and fatality rates of various irAEs, emphasizing the need for oncologists to understand both the strengths and limitations of this data for better patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance. Raschi, E., Gatti, M., Gelsomino, F., et al.[2021]

A total of 3120 adverse event cases related to avapritinib were reported to the FDA, with 44% occurring within the first 30 days of treatment, highlighting the importance of monitoring patients closely during this period.

The study found that elderly male patients are at a higher risk for serious adverse events, indicating that clinicians should exercise caution when prescribing avapritinib to this demographic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. Rong, L., Xie, M., Jiang, M., et al.[2023]

In a study of 2212 patients with advanced non-small cell lung cancer, those over 65 years old showed similar safety and efficacy outcomes when treated with bevacizumab (Avastin) combined with standard chemotherapy, compared to younger patients.

Elderly patients had comparable overall survival (14.6 months) and time to disease progression (8.2 months) as younger patients, with no significant increase in adverse events, indicating that bevacizumab is a safe and effective treatment option for older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of first-line bevacizumab plus chemotherapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer: safety of avastin in lung trial (MO19390). Laskin, J., Crinò, L., Felip, E., et al.[2015]

A large-scale analysis of 16,196 serious adverse drug reaction reports identified 36 potential safety signals associated with ibrutinib, including ischemic heart diseases and fractures, highlighting the need for careful patient monitoring.

The study found that over half of the reports resulted in hospitalization, indicating that while ibrutinib is a standard treatment for B-cell malignancies, its safety profile requires further investigation to confirm these findings in broader populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Profile of Ibrutinib: An Analysis of the WHO Pharmacovigilance Database. Allouchery, M., Tomowiak, C., Lombard, T., et al.[2021]

The combination of the PI3K inhibitor pictilisib and the aromatase inhibitor anastrozole effectively suppresses the growth of luminal B breast cancer cells, indicating a potential therapeutic strategy for this subtype of breast cancer.

This study highlights the efficacy of targeting multiple pathways in breast cancer treatment, suggesting that combining these two drugs may enhance treatment outcomes for patients with luminal B breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pictilisib Plus Anastrozole Reduces Proliferation in ER+ Breast Cancer. [2018]

In a phase IB trial involving 50 patients with advanced solid tumors, the combination of LY2780301 and gemcitabine demonstrated manageable toxicity, with the maximum tolerated dose established at 500 mg of LY2780301 and 750 mg/m2 of gemcitabine.

The treatment showed promising antitumor activity, with a disease control rate of 74% at cycle 2 and partial responses in 5% of patients, particularly in those with alterations in the PI3K/AKT/mTOR signaling pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, tolerability and antitumour activity of LY2780301 (p70S6K/AKT inhibitor) in combination with gemcitabine in molecularly selected patients with advanced or metastatic cancer: a phase IB dose escalation study. Angevin, E., Cassier, PA., Italiano, A., et al.[2022]

In a study of 226 breast cancer patients, low expression of the protein p27kip1 was linked to poorer overall survival rates specifically in those receiving taxane-based chemotherapy, suggesting it could serve as a prognostic indicator.

While low p57kip2 expression was associated with negative progesterone receptor status, it did not show a significant impact on patient outcomes, highlighting the particular importance of p27kip1 in predicting responses to taxane treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Loss of p27kip1 expression is associated with poor prognosis in patients with taxane-treated breast cancer. Kim, GJ., Kim, DH., Min, KW., et al.[2018]

In a phase I trial involving 120 patients with solid tumors, apitolisib (GDC-0980) was found to be reasonably tolerated at a dose of 30 mg, with the recommended phase 2 dose (RP2D) established at 40 mg once daily, despite some severe side effects like hyperglycemia and pneumonitis.

The treatment showed promising preliminary antitumor activity, with 10 confirmed partial responses in various cancer types, and significant modulation of target pathways was observed, indicating its potential effectiveness as a cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors. Dolly, SO., Wagner, AJ., Bendell, JC., et al.[2022]

M2698, an oral dual inhibitor targeting the p70S6K/AKT pathway, was well tolerated in 101 patients with advanced cancer, showing manageable side effects primarily related to gastrointestinal issues and fatigue.

In patients with advanced breast cancer resistant to standard therapies, M2698 demonstrated some antitumor activity, with two patients achieving partial responses when combined with trastuzumab or tamoxifen, indicating potential effectiveness in overcoming treatment resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer. Tsimberidou, AM., Shaw, JV., Juric, D., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Biomarkers in Patients with Metastatic Breast Cancer and the PRAEGNANT Study Network. [2022]

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

Impact of Precision Medicine on Clinical Outcomes: A Single-Institution Retrospective Study. [2023]

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

Improved prediction of PARP inhibitor response and identification of synergizing agents through use of a novel gene expression signature generation algorithm. [2020]

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

Improving Clinical Trial Efficiency: Thinking outside the Box. [2022]

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

Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. [2021]

6. India pubmed.ncbi.nlm.nih.gov

Risk of serious adverse event and fatal adverse event with molecular target anticancer drugs in cancer patients: A meta-analysis. [2020]

7. France pubmed.ncbi.nlm.nih.gov

Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance. [2021]

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

A post-marketing pharmacovigilance study of avapritinib: Adverse event data mining and analysis based on the United States Food and Drug Administration Adverse Event Reporting System database. [2023]

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

Safety and efficacy of first-line bevacizumab plus chemotherapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer: safety of avastin in lung trial (MO19390). [2015]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Safety Profile of Ibrutinib: An Analysis of the WHO Pharmacovigilance Database. [2021]

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

Pictilisib Plus Anastrozole Reduces Proliferation in ER+ Breast Cancer. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Safety, tolerability and antitumour activity of LY2780301 (p70S6K/AKT inhibitor) in combination with gemcitabine in molecularly selected patients with advanced or metastatic cancer: a phase IB dose escalation study. [2022]

13. Germany pubmed.ncbi.nlm.nih.gov

Loss of p27kip1 expression is associated with poor prognosis in patients with taxane-treated breast cancer. [2018]

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

Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors. [2022]

15. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer. [2022]