SHP2 Inhibitor BBP-398 in Combination With Sotorasib in Patients With Advanced Solid Tumors and a KRAS-G12C Mutation

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1 study of BBP-398, a SHP2 inhibitor, in combination with sotorasib, a KRAS-G12C inhibitor (KRAS-G12Ci), in patients with a KRAS-G12C mutation. The study involves 2 parts: Phase 1a Dose Escalation and Phase 1b Dose Expansion/Optimization.

Detailed Description
-----------------
The primary objectives for Phase 1a Dose Escalation are to evaluate safety and tolerability, and recommend a phase 1b dose (RP1bD) of the combination. The primary objectives for Phase 1b Dose Expansion/Optimization are to evaluate safety and tolerability, and the antitumor activity (defined by the ORR assessed by the investigator according to RECIST v1.1) of BBP-398 when used in combination with sotorasib across two dose regimens in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a KRAS-G12C mutation and who are KRAS-G12Ci naïve, and recommend a phase 2 dose (RP2D) of the combination.

Official Title
-----------------
A Phase 1 Study of the SHP2 Inhibitor BBP-398 (Formerly Known as IACS-15509) in Combination With the KRAS-G12C Inhibitor Sotorasib in Patients With Advanced Solid Tumors and a KRAS-G12C Mutation

Conditions
-----------------
Solid Tumor, Adult, Metastatic Solid Tumor, Metastatic NSCLC, Non Small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: BBP-398
* Drug: sotorasib


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Patients must have histologically documented, locally advanced and unresectable, or metastatic solid tumor with documentation of a KRAS-G12C mutation within 2 years prior to screening. Patients must have measurable disease by RECIST v1.1. Patients must have a minimum life expectancy of >12 weeks after start of study treatment. Patients must have progression or disease recurrence on or after all available standard of care therapies. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. Patients must have adequate organ function. Key Exclusion Criteria: Patients that have participated in an interventional clinical study within the last 4 weeks. Patients that have received radiotherapy or proton therapy with a limited field of radiation for palliation within 1 week of the start of study treatment, OR radiation to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the start of study treatment. Patients with untreated and/or active CNS metastases. Patients that have a history of allogenic bone marrow transplant.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation: BBP-398 Level 1 and sotorasib<br>BBP-398 dose Level 1 capsules administered once a day (QD) for a 28-day treatment cycle in combination with sotorasib tablets administered once a day (QD) for a 28-day treatment cycle | Drug: BBP-398<br>* BBP-398 administered orally<br>Drug: sotorasib<br>* sotorasib administered orally<br>|
| Experimental: Dose Escalation: BBP-398 Level 2 and sotorasib<br>BBP-398 dose Level 2 capsules administered once a day (QD) for a 28-day treatment cycle in combination with sotorasib tablets administered once a day (QD) for a 28-day treatment cycle | Drug: BBP-398<br>* BBP-398 administered orally<br>Drug: sotorasib<br>* sotorasib administered orally<br>|
| Experimental: Dose Escalation: BBP-398 Level 3 and sotorasib<br>BBP-398 dose Level 3 capsules administered once a day (QD) for a 28-day treatment cycle in combination with sotorasib tablets administered once a day (QD) for a 28-day treatment cycle | Drug: BBP-398<br>* BBP-398 administered orally<br>Drug: sotorasib<br>* sotorasib administered orally<br>|
| Experimental: Dose Expansion/Optimization: BBP-398 Dose Regimen 1 and sotorasib<br>BBP-398 Dose Regimen 1 capsules administered once a day (QD) for a 28-day treatment cycle in combination with sotorasib tablets administered once a day (QD) for a 28-day treatment cycle | Drug: BBP-398<br>* BBP-398 administered orally<br>Drug: sotorasib<br>* sotorasib administered orally<br>|
| Experimental: Dose Expansion/Optimization: BBP-398 Dose Regimen 2 and sotorasib<br>BBP-398 Dose Regimen 2 capsules administered once a day (QD) for a 28-day treatment cycle in combination with sotorasib tablets administered once a day (QD) for a 28-day treatment cycle | Drug: BBP-398<br>* BBP-398 administered orally<br>Drug: sotorasib<br>* sotorasib administered orally<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a Dose Escalation Primary Objective: Incidence and Severity of Treatment-Emergent Adverse Events, Serious Adverse Events, and Dose Limiting Toxicities | Number of patients experiencing treatment-emergent adverse events, serious adverse events, including changes in lab parameters, vital signs and electrocardiogram changes; duration, and severity based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Completion of 1 Cycle (28 days) | 
| Phase 1b Dose Expansion/Optimization Primary Objective: Incidence and Severity of Treatment-Emergent Adverse Events, and Serious Adverse Events | Number of patients experiencing treatment-emergent adverse events, serious adverse events, including changes in lab parameters, vital signs and electrocardiogram changes; duration, and severity based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Completion of 1 Cycle (28 days) | 
| Phase 1b Dose Expansion/Optimization Primary Objective: Overall Response Rate (ORR) | Complete Response (CR) + Partial Response (PR) rates, defined by RECIST v1.1 | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a Dose Escalation Secondary Objectives: Overall Response Rate (ORR) | Complete Response (CR) + Partial Response (PR) rates, defined by RECIST v1.1 | 8 weeks | 
| Duration of response | Defined by RECIST v1.1 | 8 weeks | 
| Progression Free Survival (PFS) | Time from treatment start to progression of disease or death by any cause | 8 weeks | 
| Overall survival (OS) | Time from treatment start to death | 8 weeks | 
| Maximum Observed Plasma Concentration (Cmax) of BBP-398 | Maximum plasma concentration of BBP-398 in combination with sotorasib | Cycle 2 Day 1 | 
| Time to Cmax (Tmax) of BBP-398 | Amount of time to reach Cmax of BBP-398 in combination with sotorasib | Cycle 2 Day 1 | 
| Area under the plasma concentration-time curve (AUC) of BBP-398 | Area under the plasma concentration versus time curve of BBP-398 in combination with sotorasib | Cycle 2 Day 1 | 
| Half-life (T1/2) of BBP-398 | Terminal half-life of BBP-398 in combination with sotorasib | Cycle 2 Day 1 | 
| Observed Maximum Plasma Concentration (Cmax) of sotorasib | Maximum plasma concentration of sotorasib in combination with BBP-398 | Cycle 2 Day 1 | 
| Time to Cmax (Tmax) of sotorasib | Amount of time to reach Cmax of sotorasib in combination with BBP-398 | Cycle 2 Day 1 | 
| Area under the plasma concentration-time curve (AUC) over dosing interval of sotorasib | Area under the plasma concentration versus time curve of sotorasib in combination with BBP-398 | Cycle 2 Day 1 | 
| Half-life (T1/2) of sotorasib | Terminal half-life of sotorasib in combination with BBP-398 | Cycle 2 Day 1 | 
| Circulating and intratumoral target engagement biomarkers of BBP-398 activity in combination with sotorasib | Raw, normalized, and/or baseline adjusted analyte signal | 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
KRAS-G12C mutation, SHP2, MAPK-pathway alterations, NSCLC