TL118 for Solid Tumors

Recruiting at 17 trial locations

Overseen By Dawei Zhang

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Teligene US

Must not be taking: Chemotherapy, Immunotherapy, TCMs, others

Disqualifiers: Active CNS metastases, Other malignancies, 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: 28 days per cycle

60 Participants Needed

Trial Summary

What is the purpose of this trial?

The main objective of the study will be to evaluate the efficacy of TL118 in participants with solid tumors harboring NTRK gene fusions

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you cannot have had any systemic anti-tumor therapy, like chemotherapy or radiation, within 3 weeks before joining the trial.

What evidence supports the effectiveness of the drug TL118 for treating solid tumors?

Research shows that FL118, a component of TL118, has strong antitumor activity by targeting multiple cancer-related proteins and is effective even in tumors resistant to other treatments. It has been shown to shrink tumors in animal models and is more effective than several existing cancer drugs. ^{1 2 3 4 5}

What makes the drug TL118 unique for treating solid tumors?

TL118 is unique because it targets multiple cancer-related proteins (survivin, Mcl-1, XIAP, and cIAP2) without relying on the p53 gene, which is often mutated in cancers. This makes it effective even in tumors resistant to other treatments, and it shows superior antitumor activity compared to many existing cancer drugs. ^{1 4 6 7 8}

Eligibility Criteria

This trial is for adults with advanced solid tumors that have a specific gene fusion called NTRK1/2/3. Participants must have tried other treatments without success or be unsuitable for standard care, and should not have used TRK inhibitors before (except briefly due to side effects). They need to be relatively active (ECOG score 0-2) and expected to live more than 3 months.

Inclusion Criteria

My blood, liver, kidney, and clotting tests are within normal ranges.

Additional requirements must be fulfilled for participation in the Study.

My cancer is advanced, has a specific gene change but no other major cancer-driving mutations.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TL118 capsule taken orally, 252 mg twice daily, for 28 days per cycle

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• TL118

Trial Overview The study tests the effectiveness of TL118, an investigational drug in capsule form, on patients with solid tumors containing NTRK gene fusions. The goal is to see how well TL118 works against these types of cancers.

Participant Groups

Group I: Single arm, Open label Experimental Treatment 1 Intervention

Participants will receive TL118 capsule taken orally with (preferred) or without food, 252 mg twice daily, 28 days for a cycle.

Who Is Running the Clinical Trial?

Teligene US

Lead Sponsor

Trials

3

Recruited

230+

Findings from Research

FL118, a novel anticancer compound identified through high throughput screening, effectively inhibits cancer cell growth at very low concentrations (less than nM) and works independently of p53 status, making it a promising treatment option for various cancers.

In vivo studies demonstrated that FL118 has superior antitumor efficacy compared to several standard chemotherapy agents, leading to tumor regression in human tumor xenograft models, while also showing manageable side effects like temporary body weight loss.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity. Ling, X., Cao, S., Cheng, Q., et al.[2021]

In patients with metastatic colorectal cancer, there is a significant decrease in certain lymphocyte populations (CD3+CD4+, CD8+CD28+, and CD19+) and an increase in activated T-cells and specific monocytes, indicating an altered immune response.

Treatment with CPT-11 (irinotecan) for 2-4 months led to a significant increase in CD3+CD4+ cell counts in patients with initially low levels, suggesting that this chemotherapy may help counteract the immunosuppressive effects of the cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of irinotecan on the phenotype of peripheral blood leukocyte populations in patients with metastatic colorectal cancer. Melichar, B., Touskova, M., Vesely, P.[2018]

FL118 is a promising new anticancer drug that targets multiple resistance mechanisms by inhibiting several antiapoptotic proteins and inducing pro-apoptotic proteins, making it effective even in cancers with dysfunctional p53, which are typically resistant to many treatments.

Unlike traditional chemotherapy drugs like irinotecan and topotecan, FL118 is not affected by the ABCG2 efflux pump, allowing it to maintain efficacy in cancer cells that express high levels of this pump, which often leads to resistance against other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticancer drug FL118 is more than a survivin inhibitor: where is the Achilles' heel of cancer? Li, F.[2021]

FL118, a new camptothecin analogue, shows superior antitumor efficacy compared to existing treatments like irinotecan and topotecan, effectively overcoming resistance in human tumor models.

Unlike traditional camptothecins, FL118's effectiveness does not depend on the expression level of the Top1 protein, suggesting that its antitumor activity may not primarily involve Top1 inhibition, although it does share similar hematopoietic toxicity mechanisms with other CPTs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topoisomerase I (Top1): a major target of FL118 for its antitumor efficacy or mainly involved in its side effects of hematopoietic toxicity? Li, F., Ling, X., Harris, DL., et al.[2020]

CPT-11 demonstrated significant tumor growth inhibition in 8 out of 15 human ovarian cancer lines and 6 out of 10 human soft-tissue sarcoma lines when administered at a daily dose of 20 mg/kg for five days.

The study suggests that more frequent administration of lower doses of CPT-11 may enhance its effectiveness in clinical settings, as the drug showed better results with a daily schedule compared to a weekly one, despite higher doses being used in the latter.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-tumor activity of CPT-11 in experimental human ovarian cancer and human soft-tissue sarcoma. Jansen, WJ., Kolfschoten, GM., Erkelens, CA., et al.[2019]

Epithelioid sarcoma (EpS) is a rare and aggressive soft-tissue cancer primarily affecting young people, with a high fatality rate of about 50% despite current treatments like surgery and chemotherapy.

The recent approval of the EZH2 inhibitor tazemetostat as a targeted therapy for EpS has not significantly improved outcomes for most patients, highlighting the urgent need for new treatment strategies and the formation of a collaborative research community to advance understanding and therapy development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translational Aspects of Epithelioid Sarcoma - Current Consensus. Grünewald, TGP., Postel-Vinay, S., Nakayama, RT., et al.[2023]

EZN-2208, a PEGylated form of the topoisomerase inhibitor SN38, was found to be generally well-tolerated in a Phase 1 study involving 30 children with relapsed or refractory solid tumors, with a maximum tolerated dose identified at 24 mg/m².

The treatment showed preliminary antitumor activity, particularly in neuroblastoma, where two out of nine evaluable patients experienced partial responses, indicating potential clinical benefit for this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 evaluation of EZN-2208, a polyethylene glycol conjugate of SN38, in children adolescents and young adults with relapsed or refractory solid tumors. Norris, RE., Shusterman, S., Gore, L., et al.[2018]

A new combination treatment strategy using the CDK4/6 inhibitor palbociclib shows promise for treating Rb-positive soft tissue sarcomas by inducing cell cycle arrest, making the cancer cells more sensitive to other treatments like doxorubicin.

This synergistic effect was confirmed in both laboratory tests and in vivo studies using patient-derived xenografts, providing strong preclinical support for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDK4/6 Inhibitors Sensitize Rb-positive Sarcoma Cells to Wee1 Kinase Inhibition through Reversible Cell-Cycle Arrest. Francis, AM., Alexander, A., Liu, Y., et al.[2022]

References

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

A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity. [2021]

2. Greece pubmed.ncbi.nlm.nih.gov

Effect of irinotecan on the phenotype of peripheral blood leukocyte populations in patients with metastatic colorectal cancer. [2018]

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

Anticancer drug FL118 is more than a survivin inhibitor: where is the Achilles' heel of cancer? [2021]

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

Topoisomerase I (Top1): a major target of FL118 for its antitumor efficacy or mainly involved in its side effects of hematopoietic toxicity? [2020]

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

Anti-tumor activity of CPT-11 in experimental human ovarian cancer and human soft-tissue sarcoma. [2019]

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

Translational Aspects of Epithelioid Sarcoma - Current Consensus. [2023]

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

Phase 1 evaluation of EZN-2208, a polyethylene glycol conjugate of SN38, in children adolescents and young adults with relapsed or refractory solid tumors. [2018]

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

CDK4/6 Inhibitors Sensitize Rb-positive Sarcoma Cells to Wee1 Kinase Inhibition through Reversible Cell-Cycle Arrest. [2022]