SHP2 Inhibitor BBP-398 in Combination With Nivolumab in Patients With Advanced Non-Small Cell Lung Cancer With a KRAS Mutation

Study Overview
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Brief Summary
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This is a Phase 1 study of BBP-398, a SHP2 inhibitor, in combination with nivolumab, a PD-1 antibody, in patients with NSCLC with a KRAS mutation. The study involves 2 parts: Phase 1a Dose Escalation and Phase 1b Dose Expansion.

Detailed Description
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The primary objective for Phase 1a Dose Escalation is to evaluate the safety, tolerability, and RP2D of BBP-398, a SHP2 inhibitor, when used in combination with nivolumab in patients with advanced NSCLC with a KRAS mutation who have failed standard of care treatment. The primary objective for Phase 1b Dose Expansion is to evaluate the antitumor activity of BBP-398, as defined by the ORR (per investigator) according to RECIST v1.1, when used in combination with nivolumab in patients with advanced NSCLC with a KRAS mutation who have failed standard of care treatment.

Official Title
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A Phase 1 Study of the SHP2 Inhibitor BBP-398 (Formerly Known as IACS-15509) in Combination With the Programmed Death Receptor-1 Blocking Antibody Nivolumab in Patients With Advanced Non-Small Cell Lung Cancer With a KRAS Mutation

Conditions
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Non Small Cell Lung Cancer, Solid Tumor

Intervention / Treatment
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* Drug: BBP-398 with nivolumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patients must have histologically documented, locally advanced and unresectable, or metastatic NSCLC with documentation of a KRAS mutation within the 1 year 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 at least one prior line of systemic therapy, which must include platinum-based doublet chemotherapy and anti-PD-(L)1 therapy. Patients must have experienced progressive or recurrent disease occurring either during treatment or within 90 days after discontinuing anti-PD-(L)1 therapy. 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 known central nervous system (CNS) tumors or active CNS metastases. Patients that have experienced progressive disease (PD) within the first 120 days of initiating treatment with an anti- PD-(L)1 agent (e.g., primary refractory). Patients that have a history of allogenic bone marrow transplant. Patients that have select known or suspected autoimmune disease. Patients that have a condition requiring systemic treatment with either corticosteroids (>10 mg prednisone equivalent) or other immunosuppressive medication within 14 days of study start. Patients that have received any live/attenuated vaccine within 30 days of first study treatment.

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 Level 1<br>Level 1 oral capsules administered in combination with nivolumab | Drug: BBP-398 with nivolumab<br>* BBP-398 administered orally once a day (QD); nivolumab administered intravenously every 4 weeks (Q4wks)<br>|
| Experimental: Dose Escalation Level 2<br>Level 2 oral capsules administered in combination with nivolumab | Drug: BBP-398 with nivolumab<br>* BBP-398 administered orally once a day (QD); nivolumab administered intravenously every 4 weeks (Q4wks)<br>|
| Experimental: Dose Escalation Level 3<br>Level 3 oral capsules administered in combination with nivolumab | Drug: BBP-398 with nivolumab<br>* BBP-398 administered orally once a day (QD); nivolumab administered intravenously every 4 weeks (Q4wks)<br>|
| Experimental: Dose Expansion<br>RP2D defined dose. Oral capsules administered in combination with nivolumab | Drug: BBP-398 with nivolumab<br>* BBP-398 administered orally once a day (QD); nivolumab administered intravenously every 4 weeks (Q4wks)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a Dose Escalation: Assess safety, tolerability, and recommended phase 2 dose (RP2D) of BBP-398 in combination with nivolumab |  | Completion of 1 Cycle (28 days) | 
| Phase 1b Dose Expansion: Assess antitumor activity of BBP-398 in combination with nivolumab | Anti-tumor activity will be defined by objective response rate (ORR) according to RECIST v1.1 | Completion of 1 Cycle (28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess preliminary antitumor activity of BBP-398 in combination with nivolumab | Anti-tumor activity will be defined by objective response rate (ORR) [escalation], duration of response (DOR) and progression free survival (PFS), as defined by RECIST v1.1. and overall survival (OS) [both escalation and expansion] | Completion of 1 Cycle (28 days) | 
| Phase 1b Dose Expansion: Assess safety and tolerability of BBP-398 at the RP2D, in combination with nivolumab |  | Completion of 1 Cycle (28 days) | 

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