TSN1611 for Cancer

Recruiting at 5 trial locations

Overseen By Tyligand Clinical Trial Info

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Tyligand Bioscience (Shanghai) Limited

Must not be taking: KRAS G12D therapy

Disqualifiers: CNS metastases, ILD, recent heart attack, others

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

Compensation: Varies

Number of Visits: Unknown

150 Participants Needed

Trial Summary

What is the purpose of this trial?

The study is a first-in-human (FIH), open-label, multi-center phase 1/2 study of TSN1611 in subjects with KRAS G12D mutant advanced solid tumors. This study will consist of a phase 1 dose escalation part and phase 2 dose expansion part.

Do I have to stop taking my current medications for the TSN1611 trial?

The trial requires that you have not had any prior systemic anti-cancer treatment within 21 days or 5 half-lives before the first dose of the study drug. It does not specify about other medications, so you should discuss your current medications with the study team.

What data supports the effectiveness of the drug TSN1611 for cancer?

Research shows that irinotecan, a component of TSN1611, has been effective in treating advanced colorectal cancer and non-small-cell lung cancer, with some patients experiencing a positive response. Additionally, combinations of irinotecan with other drugs have shown promise in treating advanced gastric cancer. ^{1 2 3 4 5}

What safety data exists for TSN1611 (irinotecan) in humans?

Irinotecan, also known as CPT-11, has been studied for safety in various cancers. Common side effects include neutropenia (low white blood cell count) and diarrhea, which can be severe and require hospitalization. However, with proper management, these side effects can be reduced. ^{6 7 8 9 10}

Research Team

Cindy Li

Principal Investigator

Tyligand Bioscience (Shanghai) Limited

Eligibility Criteria

This trial is for people with advanced solid tumors that have a specific genetic change called KRAS G12D mutation. Details on who can join or reasons for exclusion are not provided.

Inclusion Criteria

I am 18 years old or older.

Life expectancy of 3 months or more

Subject fully understands the requirements of the study and voluntarily signs the ICF

Exclusion Criteria

I haven't had cancer treatment in the last 21 days or 5 half-lives before starting the study drug.

My cancer has spread to the brain or spinal cord.

History or current evidence of any severe condition, concurrent therapy, or laboratory abnormality that might confound the interpretation of the study results, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the investigator

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Dose Escalation

Evaluation of prespecified dose levels of TSN1611 to determine the maximum tolerated dose or recommended phase 2 dose

3 weeks

Multiple visits for dose escalation and monitoring

Phase 2: Dose Expansion

Evaluation of the efficacy and safety of TSN1611 as monotherapy at the recommended dose in separate groups of patients

Up to 3 years

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• TSN1611

Trial Overview TSN1611, a new potential cancer treatment, is being tested in patients with certain advanced solid tumors. The study has two parts: finding the right dose (phase 1) and then seeing how well it works at that dose (phase 2).

Participant Groups

Group I: Phase 2: Dose expansion of TSN1611 monotherapy Experimental Treatment 1 Intervention

Phase 2 part will evaluate the efficacy and safety of TSN1611 as monotherapy at the recommended dose level in separate groups of patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer, or other solid tumors, harboring KRAS G12D mutations.

Group II: Phase 1: Dose-finding/evaluation of TSN1611 monotherapy Experimental Treatment 1 Intervention

The phase 1 part will evaluate the prespecified sequential dose levels of TSN1611 in subjects with KRAS G12D mutant advanced solid tumors to determine the recommended dose of TSN1611 for further investigation.

Who Is Running the Clinical Trial?

Tyligand Bioscience (Shanghai) Limited

Lead Sponsor

Trials

4

Recruited

500+

Tyligand Pharmaceuticals (Suzhou) Limited

Lead Sponsor

Trials

1

Recruited

150+

Findings from Research

In a retrospective study of 44 patients with fluoropyrimidine-resistant advanced colorectal cancer, irinotecan (CPT-11) showed an overall response rate of 11% and a median survival time of 12 months, indicating its potential efficacy in this challenging patient population.

The treatment was found to be safe, with no treatment-related deaths and manageable side effects, such as grade 3 anorexia and diarrhea occurring in 14% and 11% of patients, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical study of irinotecan therapy in patients with fluoropyrimidine-resistant advanced colorectal cancer]. Nishina, T., Hyodo, I., Moriwaki, T., et al.[2018]

In a study of 61 patients with metastatic non-small-cell lung cancer (NSCLC), the combination of irinotecan (CPT-11) and etoposide (VP-16) resulted in a modest overall response rate of 21.3%, with a median survival time of 10 months.

The treatment was associated with manageable toxicities, including significant hematologic side effects like leukopenia and neutropenia in 23% and 39% of patients, respectively, but was comparable in efficacy to standard cisplatin-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of irinotecan and etoposide in patients with metastatic non-small-cell lung cancer. Oshita, F., Noda, K., Nishiwaki, Y., et al.[2018]

The combination therapy of S-1 and irinotecan (CPT-11) was found to be feasible for treating advanced non-small cell lung cancer (NSCLC) in a phase I study involving 9 patients, with a recommended dose of CPT-11 set at 60 mg/m².

While no dose-limiting toxicities (DLTs) were observed at the lower dose level, some patients at the higher dose experienced significant side effects, including grade 3 diarrhea and interstitial pneumonia, indicating the importance of careful dose selection in future trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of S-1 and irinotecan combination therapy in previously treated advanced non-small cell lung cancer patients. Yoda, S., Soejima, K., Yasuda, H., et al.[2018]

In a study of 45 patients with advanced non-small-cell lung cancer (NSCLC) who had received multiple prior chemotherapy regimens, S-1 showed a disease control rate of 62.2%, with 8.9% of patients achieving a partial response.

S-1 was well tolerated with manageable side effects, as no grade 4 toxicities were observed, but the overall response rate was considered insufficient for effective treatment in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of S-1 as third-line or further chemotherapy in patients with advanced non-small-cell lung cancer. Miyoshi, S., Ito, R., Katayama, H., et al.[2021]

In a study of 23 patients with advanced gastric cancer, the combination therapy of irinotecan (CPT-11) and S-1 resulted in a promising overall response rate of 47.8% and a median time to progression of 210 days.

The treatment was associated with low rates of severe toxicity, with only 17.4% experiencing grade 3 or 4 hematological issues and 8.7% facing non-hematological toxicity, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of a combination of irinotecan and S-1 in patients with advanced gastric cancer (OGSG0002). Uedo, N., Narahara, H., Ishihara, R., et al.[2018]

CPT-11 (irinotecan) is effective for advanced colorectal cancer but has significant side effects, including high rates of neutropenia (80% of patients) and delayed diarrhea (87% of patients), with severe cases requiring hospitalization.

Recent improvements in managing CPT-11's side effects have led to a reduction in severe delayed diarrhea from 39% to 23% and febrile neutropenia from 12% to 6%, likely due to better understanding of the drug's mechanisms and enhanced patient care strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterisation and clinical management of CPT-11 (irinotecan)-induced adverse events: the European perspective. Bleiberg, H., Cvitkovic, E.[2019]

In a phase II study involving 44 patients with advanced non-small cell lung cancer (NSCLC), the combination of irinotecan (CPT-11) and cisplatin (P) demonstrated efficacy, with 22% of patients achieving a partial response and a median survival of 8 months.

The treatment was generally safe and well-tolerated, although 46% of patients experienced grade 3-4 neutropenia and 27% had grade 3-4 diarrhea, indicating that while the regimen is effective, it does carry a risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin and irinotecan (CPT-11) as second-line treatment in patients with advanced non-small cell lung cancer. Kakolyris, S., Kouroussis, C., Souglakos, J., et al.[2019]

Intestinal alkalinization significantly reduced the plasma levels of irinotecan (CPT-11) and its active metabolite SN-38 in colorectal cancer patients, with the AUC of SN-38 dropping from 107 to 56 ng.h/mL.

This treatment effectively prevented irinotecan-induced diarrhea, but it also altered the pharmacokinetics of the drug and its metabolite, indicating a complex interaction between pH levels and drug absorption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic changes of irinotecan by intestinal alkalinization in an advanced colorectal cancer patient. Hamada, A., Aoki, A., Terazaki, H., et al.[2019]

Gefitinib significantly enhances the antitumor activity of CPT-11 and its active metabolite SN-38 by inhibiting the ABCG2 transporter, which improves their effectiveness against tumors in both in vitro and in vivo models.

Coadministration of gefitinib with CPT-11 in mice led to more than a two-fold increase in the concentration of the active drug forms in tumor tissue, suggesting that this combination could allow for lower doses of CPT-11 and reduce the risk of gastrointestinal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gefitinib enhances the antitumor activity of CPT-11 in vitro and in vivo by inhibiting ABCG2 but not ABCB1: a new clue to circumvent gastrointestinal toxicity risk. Inoue, Y., Ikegami, Y., Sano, K., et al.[2018]

In a study of 25 patients with refractory or recurrent ovarian cancer, the combination of irinotecan hydrochloride (CPT-11) and cisplatin resulted in an overall response rate of 40%, with complete responses in 8% and partial responses in 32% of patients, indicating its potential efficacy as a treatment option.

The treatment was associated with significant toxicity, particularly grade 3 or 4 neutropenia occurring in 54.5% of treatment courses, but this was manageable with granulocyte colony-stimulating factor, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Irinotecan (CPT-11) combined with cisplatin in patients with refractory or recurrent ovarian cancer. Sugiyama, T., Yakushiji, M., Nishida, T., et al.[2019]

References

1. Japan pubmed.ncbi.nlm.nih.gov

[Clinical study of irinotecan therapy in patients with fluoropyrimidine-resistant advanced colorectal cancer]. [2018]

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

Phase II study of irinotecan and etoposide in patients with metastatic non-small-cell lung cancer. [2018]

3. Germany pubmed.ncbi.nlm.nih.gov

A phase I study of S-1 and irinotecan combination therapy in previously treated advanced non-small cell lung cancer patients. [2018]

4. Japan pubmed.ncbi.nlm.nih.gov

Phase II trial of S-1 as third-line or further chemotherapy in patients with advanced non-small-cell lung cancer. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Phase II study of a combination of irinotecan and S-1 in patients with advanced gastric cancer (OGSG0002). [2018]

6. England pubmed.ncbi.nlm.nih.gov

Characterisation and clinical management of CPT-11 (irinotecan)-induced adverse events: the European perspective. [2019]

7. Ireland pubmed.ncbi.nlm.nih.gov

Cisplatin and irinotecan (CPT-11) as second-line treatment in patients with advanced non-small cell lung cancer. [2019]

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

Pharmacokinetic changes of irinotecan by intestinal alkalinization in an advanced colorectal cancer patient. [2019]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Gefitinib enhances the antitumor activity of CPT-11 in vitro and in vivo by inhibiting ABCG2 but not ABCB1: a new clue to circumvent gastrointestinal toxicity risk. [2018]

10. Ireland pubmed.ncbi.nlm.nih.gov

Irinotecan (CPT-11) combined with cisplatin in patients with refractory or recurrent ovarian cancer. [2019]