NSCLC
Conditions
Brief summary
This is an open-label, non-randomized, multi-cohort, multi-center Phase Ia/Ib study for BBP-398 in combination with Osimertinib to evaluate the safety, tolerability, pharmacokinetics, determine MTD and/or RP2D, and anti-cancer activity in locally advanced or metastatic NSCLC patients with EGFR mutations and with previously 3rd generation EGFR-TKIs treated or EGFR-TKI-naive.
Interventions
DRUGBBP-398
BBP-398 (formerly known as IACS-15509) is a potent, selective, orally active allosteric inhibitor of SHP2, a tyrosine phosphatase that plays a key role in the RTK -MAPK signal transduction pathway. Key components of the MAPK pathway include the small GTPase RAS, the serine/threonine-protein kinase RAF, mitogen-activated protein kinase (MEK) and ERK. In cells, SHP2 binds to phosphorylated tyrosine residues in the intracellular domain of RTKs such as the EGFR, leading to activation of the downstream MAPK signaling pathway.
DRUGosimertinib
Osimertinib is a mutant-selective, third-generation EGFR inhibitor that targets both EGFR-activating mutations (e.g., exon 19 deletion and L858R) and EGFR-dependent on-target resistance mutation toward the 1st generation EGFR inhibitor (i.e., T790M). It is currently a first-line therapy for EGFR-mutant (EGFRmut) NSCLC, with average progression-free survival of approximately 19 months in previously untreated subjects.
Sponsors
LianBio LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Patients must have the ability to understand and the willingness to sign a written informed consent document. * Patients must be willing and able to comply with the scheduled visits, treatment plan, laboratory tests and other specified study procedures. * Age ≥18, male or female. * Patients are not suitable for surgical resection and must have histologically or cytologically confirmed advanced or metastatic NSCLC with documented EGFR sensitivity mutation (at any time since the initial diagnosis of NSCLC) to confirm susceptibility to EGFR-TKI therapy. * Patients must have measurable disease by RECIST v1.1. * ECOG performance status ≤2. * Patients must have a life expectancy of ≥12 weeks as estimated at the time of screening. * Patients must have adequate organ function.
Exclusion criteria
* Patients with a known additional malignancy that is progressing or requires active treatment. * Patients who have previously received a SHP-2 inhibitor. * Patients who are hypersensitivity to BBP-398/ Osimertinib or active or inactive excipients. * Treatment with any of the following anti-cancer therapies prior to the first dose within the stated timeframes. * Pregnant or breastfeeding female patients. * Patients with untreated symptomatic brain metastases and/or meningeal metastases.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent adverse events (TEAEs) | From the first study administration to approximately 28 days after the last study administration | Incidence and severity of treatment-emergent adverse events (TEAEs). |
| Serious adverse events (SAEs) | Administration to approximately 28 days after the last study administration | Incidence and severity of Serious adverse events (SAEs) |
| Phase Ib: ORR assessed by the investigator according to RECIST v1.1 | Every 8 weeks from first dose administration to the date of progression determined by the investigator or death due to any cause, whichever came first, assessed approximately 48 months. | ORR is defined as number of patients with confirmed responses of CR or PR, divided by the total number of treated patients with measurable disease at baseline assessed by the investigator. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Reach Maximum Plasma Concentration (Tmax) | Approximately 6 months | To characterize the pharmacokinetic parameter time to reach maximum plasma concentration (Tmax) of BBP-398 and/or Osimertinib and its metabolites. |
| Apparent total plasma clearance (CL/F) | Approximately 6 months | To characterize the pharmacokinetic parameter Apparent total plasma clearance (CL/F) of BBP-398 and/or Osimertinib and its metabolites. |
| Terminal elimination half-life (t1/2) | Approximately 6 months | To characterize the pharmacokinetic parameter Terminal elimination half-life (t1/2) of BBP-398 and/or Osimertinib and its metabolites. |
| Phase Ia: QT Interval | Approximately 6 months | Evaluated by comparing the changes using electrocardiogram in the post-dose to the pre-dose. |
| Phase Ib: DOR | Every 8 weeks from first evaluation as CR or PR to the first evaluation as PD or death of any cause, whichever came first, assessed approximately 24 months. | DOR assessed by the investigator according to RECIST v1.1. DoR is defined as time interval from the first evaluation as CR or PR to the first evaluation as PD or death of any cause assessed by the investigator (percent of patients with ≥6 months, ≥9 months, and ≥12 months DoR will be reported). |
| Phase Ib: PFS | Every 8 weeks from first evaluation as CR or PR to the first evaluation as PD or death of any cause, whichever came first, assessed approximately 24 months. | PFS assessed by the investigator according to RECIST v1.1. PFS is defined from the first date of treatment to the date of progression determined by the investigator or death due to any cause (only for dose expansion). |
| Phase Ib: OS | From the first date of treatment until date of death, assessed approximately 48 months. | including 1-year and 2-years survival rate. OS is defined from the first date of treatment until date of death (only for dose expansion). |
| Accumulation ratio (Racc) | Approximately 6 months | To characterize the pharmacokinetic parameter Accumulation ratio (Racc) of BBP-398 and/or Osimertinib and its metabolites. |
| Maximum plasma concentration (Cmax) | Approximately 6 months | To characterize the pharmacokinetic parameter Maximum plasma concentration (Cmax) of BBP-398 and/or Osimertinib and its metabolites |
| Area under the plasma concentration versus time curve (AUC) | Approximately 6 months | To characterize the pharmacokinetic parameter Area under the plasma concentration versus time curve (AUC) of BBP-398 and/or Osimertinib and its metabolites |
Countries
China
Outcome results
None listed