First-in-Human Study of the SHP2 Inhibitor BBP-398 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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A first-in-human study to evaluate the safety, tolerability and maximum tolerated dose (MTD) and establish the recommended phase 2 dose (RP2D) of BBP-398, a SHP2 inhibitor, in patients with advanced solid tumors.

Detailed Description
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The first-in-human (FIH) study of BBP-398 will be an open-label, sequential-cohort, non-randomized, Phase 1/1B study utilizing BOIN dose escalation followed by an expansion phase in patients with MAPK pathway- or RTK-driven advanced solid tumors. The primary objective is to determine safety and tolerability of BBP-398, the MTD and RP2D. The secondary objectives are to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profile, preliminary anti-tumor activity, objective response rate (ORR, complete response + partial response rate) and the duration of response (DoR) of BBP-398. The exploratory objective is to assess predictive biomarkers of response.

Official Title
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A Phase 1/1B First-in-Human Study of the SHP2 Inhibitor BBP-398 (Formerly Known as IACS-15509) in Patients With Advanced Solid Tumors

Conditions
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Tumor, Solid

Intervention / Treatment
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* Drug: BBP-398 (Formerly known as IACS-15509)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Male and non-pregnant females >18 years old. Patients must have a diagnosis of advanced (primary or recurrent) or metastatic solid tumor with MAPK-pathway alterations as assessed by clinically validated and/or FDA-approved molecular diagnostic and no available standard of care or curative therapies (MAPK-pathway alterations include, for example KRASG12C mutant, EGFR-mutant). Dose expansion only: Patients with specific genomically defined tumor types will be recruited. Patients must have measurable disease by RECIST v1.1. Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2. Patients must have adequate organ function. Patients must have the ability to understand and the willingness to sign a written informed consent document prior to the initiation of the study and any study procedures. Patients must be willing and able to comply with the scheduled visits, treatment plan, laboratory tests and other specified study procedures. Key Exclusion Criteria Patients with known active Hepatitis B, Hepatitis C infection, or HIV infection. Patients with a history of CVA, myocardial infarction or unstable angina within the previous 6 months before starting therapy. Patients with clinically significant cardiac disease. Patients with tumors harboring known activating mutations. Patients with a known additional malignancy that is progressing or requires active treatment. Patients with known central nervous system (CNS) tumors. Patients with known active CNS metastases and/or carcinomatous meningitis. Patients who have previously received a SHP2 inhibitor. Patients with inability to swallow oral medications or with gastrointestinal illness that would preclude the absorption of an oral agent. Patients on dialysis. Patients with a life expectancy of ≤12 weeks after the start of IP according to the investigator's judgement. Patients with known intolerance/hypersensitivity to BBP-398 or its excipients.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Oral capsules taken in escalating levels to determine MTD/RP2D. Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD). | Drug: BBP-398 (Formerly known as IACS-15509)<br>* oral capsules<br>|
| Experimental: Dose Expansion<br>Oral capsules administered at MTD/RP2D defined dose. Each treatment cycle will be 28 days in duration with BBP-398 administered, once daily (QD) Cohort A: Advanced or metastatic KRAS mutant solid tumor Cohort B: Advanced solid tumor with NF1 loss-of-function (LOF) or metastatic BRAF class II/III mutant solid tumor | Drug: BBP-398 (Formerly known as IACS-15509)<br>* oral capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of Maximum Tolerated Dose (MTD) and establish the RP2D of BBP-398. | The MTD will be based on DLT. | Completion of 1 Cycle ( 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of anti-tumor activity of BBP-398 | Anti-tumor activity will be defined by objective response rate (ORR2, complete response + partial response rate) and duration of response (DOR3) | After 1 dose of BBP-398 | 
| Maximum observed plasma concentration (Cmax) of BBP-398 | Maximum plasma concentration of BBP-398 after single and multiple dose administration of BBP-398 | Approximately 6 weeks | 
| Time to reach Cmax (Tmax) of BBP-398 | The amount of time to reach Cmax after single and multiple dose administration of BBP-398 | Approximately 6 weeks | 
| Terminal half-life (t1/2) of BBP-398 | Terminal half-life (t1/2) after single and multiple dose administration of BBP-398 | Approximately 6 weeks | 
| Area under the plasma concentration-time curve (AUC) of BBP-398 | Area under the plasma concentration versus time curve after single and multiple dose administration of BBP-398 | Approximately 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, MAPK-pathway alterations