Malignant Neoplasm
Conditions
Keywords
solid tumor, KRAS G12D mutation, pancreatic cancer, colorectal cancer, non-small cell lung cancer, malignant neoplasm
Brief summary
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.
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.
Interventions
DRUGTSN1611
TSN1611 will be administered at the assigned dose level, orally, until disease progression or intolerable toxicity.
Sponsors
Tyligand Pharmaceuticals (Suzhou) Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicities (DLTs) in phase 1 part | 21 days | 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. |
| Objective response rate (ORR) in phase 2 part | Up to 3 years | To evaluate the anti-tumor activity of TSN1611 using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events | Up to 3 years | To assess the safety profile and tolerability of TSN1611 as monotherapy in subjects with KRAS G12D mutant advanced solid tumors. |
| Area under the plasma concentration-time curve (AUC) | 9 weeks | To characterize the pharmacokinetic (PK) profile of TSN1611. |
| Maximum blood concentrations (Cmax) | 9 weeks | To characterize the PK profile of TSN1611. |
| Time to maximum blood concentration (Tmax) | 9 weeks | To characterize the PK profile of TSN1611. |
| Duration of response (DOR) | Up to 3 years | To evaluate the anti-tumor activity of TSN1611 using RECIST version 1.1. |
| Time to response (TTR) | Up to 3 years | To evaluate the anti-tumor activity of TSN1611 using RECIST version 1.1. |
| Disease control rate (DCR) | Up to 3 years | To evaluate the anti-tumor activity of TSN1611 using RECIST version 1.1. |
| Progression free survival (PFS) | Up to 3 years | To evaluate the anti-tumor activity of TSN1611 using RECIST version 1.1. |
| Overall survival | Up to 3 years | — |
Countries
China, United States
Contacts
CONTACTTyligand Clinical Trial Info
STUDY_DIRECTORCindy Li
Tyligand Bioscience (Shanghai) Limited
Outcome results
None listed