NRAS/KRAS Mutated Advanced or Metastatic Refractory Solid Tumors
Conditions
Brief summary
This is a Phase I, open-label, dose escalation study of LNP3794 (BI3011441) in subjects with NRAS/KRAS mutated advanced or metastatic refractory solid tumors. The purpose of this study is to evaluate the safety/tolerability, pharmacokinetic and pharmacodynamic profile of the orally administered LNP3794 (BI3011441) as monotherapy at selected dose levels.
Interventions
DRUGLNP3794
LNP3794 capsules administered orally once daily
Sponsors
Lupin Ltd.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subjects ≥18 years of age 2. Pathologically documented, locally-advanced or metastatic solid malignancy with NRAS or KRAS mutation 3. At least one target lesion that can be measured per RECIST version 1.1 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 5. Adequate organ function (bone marrow, hepatic, renal, cardiovascular) 6. Documented disease progression despite appropriate prior standard therapies or subjects for whom no standard therapy exists for their tumor type and disease stage 7. Reproductive criteria (as defined in the protocol)
Exclusion criteria
1. Subjects with symptomatic central nervous system (CNS) metastases 2. History of another primary malignancy, with the exception of locally excised nonmelanoma skin cancer and carcinoma in situ of uterine cervix 3. Known active hepatitis B infection or hepatitis C infection 4. Known pre-existing interstitial lung disease 5. Known diagnosis of human immunodeficiency virus (HIV) infection 6. History or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy; or known risk factors for RVO or central serous retinopathy 7. Any severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the Investigator, Sponsor, or contract research organization, could affect the subject's participation in the study 8. Impaired cardiac function or clinically significant cardiac diseases 9. Previous treatment with RAS or MEK targeting agents 10. Chemotherapy, biologic therapy, immunotherapy, radiotherapy, or investigational agents within 5 half-lives or within 4 weeks (whichever is longer) prior to administration of the first dose of study treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of subjects with dose limiting toxicities (DLTs) at each dose level during the first cycle | up to Day 28 | Dose limiting toxicities will be evaluated through the first cycle (each cycle is 28 days) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of LNP3794 | Cycle 1 (each cycle is 28 days) Day 1 and Day 14 | Cmax is the maximum observed plasma concentration. |
| Number of subjects with DLTs during the entire on-treatment period | up to 2 years | Dose limiting toxicities will be evaluated through the entire on-treatment period |
| Number of subjects with Grade ≥3 treatment-related adverse events (AEs) | up to 2 years | Grade ≥3 treatment-related adverse events will be evaluated through the entire on-treatment period |
| Number of subjects with treatment-related AEs at each dose level | up to 2 years | Treatment-related AEs at each dose level will be evaluated through the entire on-treatment period |
| Area under the concentration-time curve from time zero to the end of dosing interval (AUC[0-tau]) | Cycle 1 (each cycle is 28 days) Day 1 to 2 and Day 14 to 15 | AUC\[0-tau\] is the measure of plasma drug concentration from time zero to the end of dosing interval. |
| Time to maximum concentration (Tmax) | Cycle 1 (each cycle is 28 days) Day 1 and Day 14 | Tmax is the time to reach maximum plasma concentration. |
| Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUC[0-last]) | Cycle 1 (each cycle is 28 days) Day 1 and Day 14 | AUC\[0-last\] is the measure of plasma drug concentration from time zero to the time of last quantifiable concentration. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in pERK levels | Baseline and Cycle 1 (each cycle is 28 days) Day 14 | Change from baseline in pERK levels will be evaluated |
| Objective response rate (ORR) and disease control rate (DCR) | up to 2 years | Objective response rate (ORR) and disease control rate (DCR) will be determined using response evaluation criteria in solid tumors (RECIST) v1.1. |
Countries
Belgium, Netherlands, United Kingdom
Outcome results
None listed