A Study of TSN1611 Treating Patients With Advanced Solid Tumors Harboring KRAS G12D Mutation

Phase 1/2 Study of TSN1611 in Subjects With Advanced Solid Tumors Harboring KRAS G12D Mutation

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. This study will evaluate the efficacy of TSN1611 at RP2D(s) through ORR using RECIST version 1.1, and determine and confirm the MTD/RP2D for TSN1611 in combination with cetuximab, in combination with cetuximab and mFOLFOX6, in combination with gemcitabine and albumin-bound paclitaxel in subjects with selected solid tumors.

Study Overview

• Status: Recruiting
• Conditions: Malignant Neoplasm
• Intervention / Treatment: Drug: TSN1611; Drug: TSN1611; Drug: TSN1611; Drug: TSN1611

Detailed Description

Phase 1 Part of TSN1611 Monotherapy:

The phase 1 part will evaluate the prespecified dose levels of TSN1611. Dose escalation will continue until up to the highest planned dose or the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) is determined. Dose optimization could be performed as indicated by the emerging data.

Phase 2 Part of TSN1611 Monotherapy:

hase 2 part of TSN1611 monotherapy will evaluate the efficacy and safety of TSN1611 as monotherapy at the RP2D until disease progression or unacceptable toxicity in separate groups of patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer, or other solid tumors, harboring KRAS G12D mutations.

Phase 1b/2 Part of TSN1611 Combination Therapy:

This part will consist of the investigations of 3 combined therapies (Cohort A, B and C). In each cohort, there will be a Phase 1b Safety Lead-in Stage to determine the dose of TSN1611 for the combination therapy (this part will be conducted in selected sites), followed by the Phase 2 Expansion Stage to enroll more subjects to determine the efficacy in different cohorts.

• Study Type: Interventional
• Enrollment (Estimated): 440
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Tyligand Clinical Trial Info; Phone Number: +86 021-50720081; Email: clinical_trial@tyligand.com

Study Locations

• China
  • Beijing, China, 100142
    • Recruiting
    • Beijing Cancer Hospital, Beijing, China
    • Contact: Lin Shen
    • Principal Investigator: Lin Shen, MD
  • Shanghai, China, 200030
    • Recruiting
    • Shanghai Chest Hospital, Shanghai, China
    • Principal Investigator: Shun Lu, MD
    • Contact: Shun Lu
  • Shanghai, China, 200032
    • Recruiting
    • Shanghai Zhongshan Hospital, Shanghai, China
    • Principal Investigator: Tianshu Liu, MD
    • Contact: Tianshu Liu
  • Anhui
    • Hefei, Anhui, China
      • Recruiting
      • Anhui Provincial Cancer Hospital
      • Principal Investigator: Yueyin Pan
      • Contact: Yueyin Pan
  • Beijing Municipality
    • Beijing, Beijing Municipality, China
      • Recruiting
      • Beijing Cancer Hospital
      • Contact: Minglei Zhuo
      • Principal Investigator: Minglei Zhuo
  • Guangdong
    • Guangzhou, Guangdong, China
      • Recruiting
      • The First Affiliated Hospital of Guangzhou Medical University
      • Contact: Chengzhi Zhou
      • Principal Investigator: Chengzhi Zhou
  • Hubei
    • Wuhan, Hubei, China
      • Recruiting
      • Hubei Cancer Hospital
      • Principal Investigator: Bin Yang
      • Contact: Bin Yang
  • Hunan
    • Changsha, Hunan, China
      • Recruiting
      • Hunan Cancer Hospital
      • Contact: Lin Wu, MD
      • Principal Investigator: Lin Wu
  • Jiang
    • Nanchang, Jiang, China
      • Recruiting
      • The First Affiliated Hospital of Nanchang University - Donghu District
      • Principal Investigator: Yong Li
      • Contact: Yong Li
      • Contact: Pu Li
      • Principal Investigator: Pu Li
  • Shandong
    • Linyi, Shandong, China
      • Recruiting
      • Linyi Cancer Hospital
      • Principal Investigator: Jianhua Shi
      • Contact: Janhua Shi
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China
      • Recruiting
      • Shanghai Tenth People's Hospital
      • Principal Investigator: Xiaojun Chen
      • Contact: Xiaojun Chen
  • Sichuan
    • Chengdu, Sichuan, China
      • Recruiting
      • West China Hospital, Sichuan University
      • Contact: Ma Ji
      • Principal Investigator: Ji Ma
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Recruiting
      • The Second Affiliated Hospital of Zhejiang University School of Medicine
      • Principal Investigator: Ying Yuan
      • Contact: Yuan Ying
    • Hangzhou, Zhejiang, China
      • Recruiting
      • Sir Run Run Shaw Hospital - Zhejiang University School of Med
      • Contact: Haizhou Lou
      • Principal Investigator: Haizhou Lou
    • Hangzhou, Zhejiang, China
      • Recruiting
      • The First Affiliated Hospital - Zhejiang University School of Medicine
      • Principal Investigator: Jianya Zhou
      • Contact: Jianya Zhou
    • Taizhou, Zhejiang, China
      • Recruiting
      • Taizhou Hospital of Zhejiang Province
      • Contact: Dongqing Lv
      • Principal Investigator: Dongqing LV
• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Recruiting
      • MD Anderson Cancer Center
      • Contact: Siqing Fu, MD,PhD
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • NEXT Oncology
      • Contact: David Sommerhalder, MD
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • NEXT Virginia
      • Contact: Alexander Spira, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Subjects must meet all the following inclusion criteria to be eligible for participation in this study:

• The subject fully understands the requirements of the study and voluntarily signs the ICF.
• At least 18 years of age at the time of informed consent.≤ 75 years of age for Cohort B and C.
• Life expectancy of 3 months or more.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Phase 1 part (1a/1b) of Monotherapy:

Subjects with histologically or cytologically confirmed locally advanced or metastatic solid tumor harboring KRAS G12D mutation; subjects must be refractory or intolerable to standard treatment, or have no standard treatment available, or the subject is ineligible or declines standard treatment.

Phase 2 part of TSN1611 Monotherapy:

Subjects with histologically or cytologically confirmed locally advanced or metastatic PDAC、CRC and NSCLC harboring KRAS G12D mutation; According to the requirements of different combined cohorts, the number of previous treatments is taken into account.

• Patients with adequate cardiac, liver, renal function, etc.

Exclusion Criteria

Subjects will be excluded if they meet any of the following criteria:

• Leptomeningeal disease or Active central nervous system (CNS) metastases.
• Prior systemic anti-cancer treatment within 21 days or 5 half-lives (whichever is shorter will be used as the criteria) prior to the first dose of study drug.
• Radical radiation within 4 weeks prior to the first dose of study drug; palliative radiotherapy within 1 week prior to the first dose of study drug.
• Any unresolved Grade 2 or higher toxicity from previous anticancer therapy except alopecia.
• Has participated in a study of investigational agent and received the investigational agent within 21 days or 5 half-lives, if known (whichever is shorter) prior to the first dose of study drug.
• History of interstitial lung disease (ILD), drug induced IDL, or current active pneumonitis, radiation pneumonitis requiring therapeutic intervention, or uncontrolled other lung disease.
• Any of the following in the past 6 months: myocardial infarction, unstable angina, symptomatic congestive heart failure, stroke or transient ischemic attack, pulmonary embolism.
• Prior treatment with KRAS G12D targeted therapy.
• Has a 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1: Dose-finding/evaluation of TSN1611 monotherapy; 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.	Drug: TSN1611; TSN1611 will be administered at the assigned dose level, orally, until disease progression or intolerable toxicity.; Drug: TSN1611; TSN1611 BID, Cetuximab will be administered via intravenous infusion at a dose of 500 mg/m² every 2 weeks.; Drug: TSN1611; TSN1611 BID, Paclitaxel (albumin-bound) at 125 mg/m² and gemcitabine at 1000 mg/m² will be administered via intravenous infusion on Days 1, 8, and 15 of each 4-week cycle.; Other Names: Paclitaxel (albumin-bound); Drug: TSN1611; TSN1611 BID everyday and Patients will be administered with mFOLFOX6 on Days 1 and 2, every 2 weeks.; Other Names: leucovorin; fluorouracil; Oxaliplatin injection
Experimental: Phase 2: Dose expansion of TSN1611 monotherapy; 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.	Drug: TSN1611; TSN1611 will be administered at the assigned dose level, orally, until disease progression or intolerable toxicity.; Drug: TSN1611; TSN1611 BID, Cetuximab will be administered via intravenous infusion at a dose of 500 mg/m² every 2 weeks.; Drug: TSN1611; TSN1611 BID, Paclitaxel (albumin-bound) at 125 mg/m² and gemcitabine at 1000 mg/m² will be administered via intravenous infusion on Days 1, 8, and 15 of each 4-week cycle.; Other Names: Paclitaxel (albumin-bound); Drug: TSN1611; TSN1611 BID everyday and Patients will be administered with mFOLFOX6 on Days 1 and 2, every 2 weeks.; Other Names: leucovorin; fluorouracil; Oxaliplatin injection
Experimental: Dose of Phase 1b/2 part of TSN1611 combination therapy-Cohort A; Cohort A: TSN1611 combined with cetuximab treating subjects with advanced solid tumors harboring KRAS G12D mutation:	Drug: TSN1611; TSN1611 will be administered at the assigned dose level, orally, until disease progression or intolerable toxicity.; Drug: TSN1611; TSN1611 BID, Cetuximab will be administered via intravenous infusion at a dose of 500 mg/m² every 2 weeks.; Drug: TSN1611; TSN1611 BID, Paclitaxel (albumin-bound) at 125 mg/m² and gemcitabine at 1000 mg/m² will be administered via intravenous infusion on Days 1, 8, and 15 of each 4-week cycle.; Other Names: Paclitaxel (albumin-bound); Drug: TSN1611; TSN1611 BID everyday and Patients will be administered with mFOLFOX6 on Days 1 and 2, every 2 weeks.; Other Names: leucovorin; fluorouracil; Oxaliplatin injection
Experimental: Dose of Phase 1b/2 part of TSN1611 combination therapy-Cohort B; Cohort B: TSN1611 combined with GnP regimen (i.e., gemcitabine and nab-paclitaxel) treating subjects with advanced PDAC with KRAS G12D mutation who received no prior systemic treatment in the advanced setting.	Drug: TSN1611; TSN1611 will be administered at the assigned dose level, orally, until disease progression or intolerable toxicity.; Drug: TSN1611; TSN1611 BID, Cetuximab will be administered via intravenous infusion at a dose of 500 mg/m² every 2 weeks.; Drug: TSN1611; TSN1611 BID, Paclitaxel (albumin-bound) at 125 mg/m² and gemcitabine at 1000 mg/m² will be administered via intravenous infusion on Days 1, 8, and 15 of each 4-week cycle.; Other Names: Paclitaxel (albumin-bound); Drug: TSN1611; TSN1611 BID everyday and Patients will be administered with mFOLFOX6 on Days 1 and 2, every 2 weeks.; Other Names: leucovorin; fluorouracil; Oxaliplatin injection
Experimental: Dose of Phase 1b/2 part of TSN1611 combination therapy-Cohort C; Cohort C: TSN1611 combined with cetuximab and mFOLFOX6 regimen (i.e., fluorouracil, leucovorin, oxaliplatin) treating subjects with advanced CRC with KRAS G12D mutation who received no prior systemic treatment in the advanced setting.	Drug: TSN1611; TSN1611 will be administered at the assigned dose level, orally, until disease progression or intolerable toxicity.; Drug: TSN1611; TSN1611 BID, Cetuximab will be administered via intravenous infusion at a dose of 500 mg/m² every 2 weeks.; Drug: TSN1611; TSN1611 BID, Paclitaxel (albumin-bound) at 125 mg/m² and gemcitabine at 1000 mg/m² will be administered via intravenous infusion on Days 1, 8, and 15 of each 4-week cycle.; Other Names: Paclitaxel (albumin-bound); Drug: TSN1611; TSN1611 BID everyday and Patients will be administered with mFOLFOX6 on Days 1 and 2, every 2 weeks.; Other Names: leucovorin; fluorouracil; Oxaliplatin injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicities (DLTs) in phase 1 part	To determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose(s) (RP2D[s]) of TSN1611 as monotherapy in subjects with KRAS G12D mutant advanced solid tumors.	21 days
Objective response rate (ORR) in phase 2 part	To evaluate the anti-tumor activity of TSN1611 using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		Up to 3 years
Adverse events	To assess the safety profile and tolerability of TSN1611 as monotherapy in subjects with KRAS G12D mutant advanced solid tumors.	Up to 3 years
Area under the plasma concentration-time curve (AUC)	To characterize the pharmacokinetic (PK) profile of TSN1611.	9 weeks
Maximum blood concentrations (Cmax)	To characterize the PK profile of TSN1611.	9 weeks
Time to maximum blood concentration (Tmax)	To characterize the PK profile of TSN1611.	9 weeks
Duration of response (DOR)	To evaluate the anti-tumor activity of TSN1611 using RECIST version 1.1.	Up to 3 years
Time to response (TTR)	To evaluate the anti-tumor activity of TSN1611 using RECIST version 1.1.	Up to 3 years
Disease control rate (DCR)	To evaluate the anti-tumor activity of TSN1611 using RECIST version 1.1.	Up to 3 years
Progression free survival (PFS)	To evaluate the anti-tumor activity of TSN1611 using RECIST version 1.1.	Up to 3 years

Collaborators and Investigators

• Sponsor: Tyligand Pharmaceuticals (Suzhou) Limited
• Investigators: Study Director: Cindy Li, Tyligand Bioscience (Shanghai) Limited

Study record dates

Study Major Dates

• Study Start (Actual): April 29, 2024
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): April 30, 2027

Study Registration Dates

• First Submitted: April 18, 2024
• First Submitted That Met QC Criteria: April 23, 2024
• First Posted (Actual): April 26, 2024

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: colorectal cancer; non-small cell lung cancer; pancreatic cancer; solid tumor; malignant neoplasm; KRAS G12D mutation
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Intestinal Diseases; Respiratory Tract Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Neoplasms; Colorectal Neoplasms; Pancreatic Neoplasms; Carcinoma, Non-Small-Cell Lung; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Enzymes and Coenzymes; Coordination Complexes; Pyrimidines; Health Care Economics and Organizations; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Uracil; Pyrimidinones; Coenzymes; Economics; Oxaliplatin; Fluorouracil; Leucovorin; Taxes
• Other Study ID Numbers: TSN1611-2023-101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No